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    Clinical Trial Results:
    A Phase III, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of alpelisib (BYL719) in combination with nab-paclitaxel in patients with advanced triple negative breast cancer with either phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) mutation or phosphatase and tensin homolog protein (PTEN) loss without PIK3CA mutation

    Summary
    EudraCT number
    		 2019-002637-11
    Trial protocol
    		 HU   FR   SK   DE   GB   IT   NO   AT   BG   SI   PL   HR   GR   RO   PT  
    Global end of trial date
    05 Feb 2026

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2026
    First version publication date
    29 Oct 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBYL719H12301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04251533
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Lichtstrasse 35, Basel, Switzerland, 4056
    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
    05 Feb 2026
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2026
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to determine whether treatment with alpelisib in combination with nab-paclitaxel is safe and effective in subjects with advanced triple negative breast cancer (aTNBC) who carry either a PIK3CA mutation (Study Part A) or have PTEN loss (Study Part B1) or PTEN loss without PIK3CA mutation (Study Part B2)
    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
    08 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    China: 19
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    India: 5
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Malaysia: 14
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Slovenia: 1
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Türkiye: 8
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    137
    EEA total number of subjects
    39
    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)
    104
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 137 participants were enrolled from 30 countries across Europe, Asia-Pacific, North America, South America, and Africa.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: alpelisib + nab-paclitaxel
    Arm description
    		 Participants received alpelisib 300 mg orally in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nab-paclitaxel
    Investigational medicinal product code
    Other name
    abraxane
    Pharmaceutical forms
    Powder for suspension for injection, Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle

    Investigational medicinal product name
    alpelisib
    Investigational medicinal product code
    Other name
    BYL719
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg orally, once per day (QD), tablets

    Arm title
    		 Part A: placebo + nab-paclitaxel
    Arm description
    		 Participants received placebo in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.
    Arm type
    		 Placebo

    Investigational medicinal product name
    nab-paclitaxel
    Investigational medicinal product code
    Other name
    abraxane
    Pharmaceutical forms
    Powder for suspension for injection, Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg orally, once per day (QD), tablets

    Arm title
    		 Part B1: alpelisib + nab-paclitaxel
    Arm description
    		 Participants received alpelisib 300 mg administered orally in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nab-paclitaxel
    Investigational medicinal product code
    Other name
    abraxane
    Pharmaceutical forms
    Powder for suspension for injection, Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle

    Investigational medicinal product name
    alpelisib
    Investigational medicinal product code
    Other name
    BYL719
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg orally, once per day (QD), tablets

    Number of subjects in period 1
    		Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel Part B1: alpelisib + nab-paclitaxel
    Started
    52
    50
    35
    Completed
    0
    0
    0
    Not completed
    52
    50
    35
         Adverse event, serious fatal
    6
    1
    3
         Physician decision
    3
    5
    5
         Subject decision
    1
    4
    1
         Adverse event, non-fatal
    2
    2
    1
         Study terminated by sponsor
    -
    2
    -
         Progressive disease
    40
    36
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: alpelisib + nab-paclitaxel
    Reporting group description
    		 Participants received alpelisib 300 mg orally in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.

    Reporting group title
    Part A: placebo + nab-paclitaxel
    Reporting group description
    		 Participants received placebo in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.

    Reporting group title
    Part B1: alpelisib + nab-paclitaxel
    Reporting group description
    		 Participants received alpelisib 300 mg administered orally in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.

    Reporting group values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel Part B1: alpelisib + nab-paclitaxel Total
    Number of subjects
    		 52 50 35 137
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 42 32 30 104
        From 65-84 years
    		 10 18 5 33
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.8 ( 9.76 ) 59.1 ( 11.34 ) 48.4 ( 12.21 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 52 49 35 136
        Male
    		 0 1 0 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 1 1
        Asian
    		 17 19 10 46
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 0 1 2
        White
    		 32 30 23 85
        More than one race
    		 1 1 0 2
        Unknown or Not Reported
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part A: alpelisib + nab-paclitaxel
    Reporting group description
    		 Participants received alpelisib 300 mg orally in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.

    Reporting group title
    Part A: placebo + nab-paclitaxel
    Reporting group description
    		 Participants received placebo in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.

    Reporting group title
    Part B1: alpelisib + nab-paclitaxel
    Reporting group description
    		 Participants received alpelisib 300 mg administered orally in combination with nab-paclitaxel 100 mg/m² administered intravenously on Days 1, 8, and 15 of each 28-day treatment cycle.

    Primary: Progression-free Survival (PFS) Per Investigator Assessment in Study Part A

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    End point title
    		 Progression-free Survival (PFS) Per Investigator Assessment in Study Part A [1]
    End point description
    PFS was defined as time from the date of randomization to the date of the first documented progressive disease (PD) or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm^2. PFS was censored at the date of the last adequate tumor assessment, if no PFS event was observed prior to the analysis cut-off date.
    End point type
    Primary
    End point timeframe
    Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
    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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    52
    50
    Units: months
        median (confidence interval 95%)
    7.2 (3.71 to 8.57)
    5.6 (3.75 to 12.68)
    Statistical analysis title
    		 PFS in Study Part A
    Comparison groups
    Part A: alpelisib + nab-paclitaxel v Part A: placebo + nab-paclitaxel
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 2.41

    Primary: Overall Response Rate (ORR) Based on Local Radiology Assessments in Participants with Measurable Disease at Baseline in Study Part B1

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    End point title
    		 Overall Response Rate (ORR) Based on Local Radiology Assessments in Participants with Measurable Disease at Baseline in Study Part B1 [2] [3]
    End point description
    ORR was defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1. BOR was defined as the best response recorded from the start of the study treatment until progressive disease (PD)/recurrence. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm^2.
    End point type
    Primary
    End point timeframe
    Up to 6 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only Descriptive analysis performed
    [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: Endpoint only applicable to Study Part B1
    End point values
    		 Part B1: alpelisib + nab-paclitaxel
    Number of subjects analysed
    35
    Units: percentage of participants
        number (confidence interval 95%)
    14.3 (4.8 to 30.3)
    No statistical analyses for this end point

    Secondary: Overall Survival in Study Part A

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    End point title
    		 Overall Survival in Study Part A [4]
    End point description
    Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If a participant was not known to have died, OS was censored at the latest date the participant was known to be alive (on or before the cut-off date), i.e., the last known date the participant was alive (last contact date).
    End point type
    Secondary
    End point timeframe
    Up to 68 months
    Notes
    [4] - 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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    52
    50 [5]
    Units: Months
        median (confidence interval 95%)
    14.9 (10.68 to 23.49)
    27.6 (10.22 to 999)
    Notes
    [5] - 95% CI upper limit not estimable due to insufficient events.
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) with Confirmed Response in Study Part A

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    End point title
    		 Overall Response Rate (ORR) with Confirmed Response in Study Part A [6]
    End point description
    ORR with confirmed response was the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), as per local review and according to RECIST 1.1. BOR was defined as the best response recorded from the start of the study treatment until progressive disease (PD)/recurrence. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
    Notes
    [6] - 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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    52
    50
    Units: percentage of participants
        number (confidence interval 95%)
    40.4 (27.0 to 54.9)
    34.0 (21.2 to 48.8)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) with Confirmed Response in Study Part A

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    End point title
    		 Clinical Benefit Rate (CBR) with Confirmed Response in Study Part A [7]
    End point description
    Clinical benefit rate (CBR) was defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
    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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    52
    50
    Units: percentage of participants
        number (confidence interval 95%)
    50.0 (35.8 to 64.2)
    44.0 (30.0 to 58.7)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) with Confirmed Response in Study Part B1

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    End point title
    		 Clinical Benefit Rate (CBR) with Confirmed Response in Study Part B1 [8]
    End point description
    Clinical benefit rate (CBR) was defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    Notes
    [8] - 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: Endpoint only applicable to Study Part B1
    End point values
    		 Part B1: alpelisib + nab-paclitaxel
    Number of subjects analysed
    35
    Units: percentage of participants
        number (confidence interval 95%)
    25.7 (12.5 to 43.3)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) in Study Part A

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    End point title
    		 Time to Response (TTR) in Study Part A [9]
    End point description
    Time to response (TTR) was defined as the time from the date of randomization/enrolment to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). CR and PR were based on tumor response data as per local review and according to RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
    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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    52 [10]
    50 [11]
    Units: months
        median (confidence interval 95%)
    999 (4.14 to 999)
    999 (999 to 999)
    Notes
    [10] - Median and upper 95% CI limit not estimable due to insufficient number of events.
    [11] - Median and 95% CI limits were not estimable due to an insufficient number of events.
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) in Study Part B1

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    End point title
    		 Time to Response (TTR) in Study Part B1 [12]
    End point description
    Time to response (TTR) was defined as the time from the date of randomization/enrolment to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response was used, not date of confirmation). CR and PR were based on tumor response data as per local review and according to RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    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: Endpoint only applicable to Study Part B1
    End point values
    		 Part B1: alpelisib + nab-paclitaxel
    Number of subjects analysed
    35 [13]
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    Notes
    [13] - Median and 95% CI limits were not estimable due to an insufficient number of events.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) with Confirmed Response in Study Part A

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    End point title
    		 Duration of Response (DOR) with Confirmed Response in Study Part A [14]
    End point description
    Duration of response (DOR) with confirmed response only applied to participants whose best overall response (BOR) was confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date was the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date was defined as the date of the first documented progressive disease (PD) or death due to underlying cancer. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
    Notes
    [14] - 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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    21
    17 [15]
    Units: months
        median (confidence interval 95%)
    7.39 (5.59 to 9.53)
    999 (10.55 to 999)
    Notes
    [15] - Median and upper 95% CI limit not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) with Confirmed Response in Study Part B1

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    End point title
    		 Duration of Response (DOR) with Confirmed Response in Study Part B1 [16]
    End point description
    Duration of response (DOR) with confirmed response only applied to participants whose best overall response (BOR) was confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date was the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date was defined as the date of the first documented progressive disease (PD) or death due to underlying cancer. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Up to approximately 20 months
    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: Endpoint only applicable to Study Part B1
    End point values
    		 Part B1: alpelisib + nab-paclitaxel
    Number of subjects analysed
    5 [17]
    Units: months
        median (confidence interval 95%)
    11.04 (7.46 to 999)
    Notes
    [17] - Upper 95% CI limit not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Overall Survival in Study Part B1

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    End point title
    		 Overall Survival in Study Part B1 [18]
    End point description
    Overall survival for Part B1 was defined as the number of participants who were alive at the end of the post-treatment period.
    End point type
    Secondary
    End point timeframe
    Up to approximately 68 months.
    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: Endpoint only applicable to Study Part B1
    End point values
    		 Part B1: alpelisib + nab-paclitaxel
    Number of subjects analysed
    35
    Units: Participants
    21
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) Per Investigator Assessment in Study Part B1

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    End point title
    		 Progression-free Survival (PFS) Per Investigator Assessment in Study Part B1 [19]
    End point description
    PFS was defined as time from the date of enrolment to the date of the first documented progressive disease (PD) or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. PD=At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm^2. PFS was censored at the date of the last adequate tumor assessment, if no PFS event was observed prior to the analysis cut-off date.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    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: Endpoint only applicable to Study Part B1
    End point values
    		 Part B1: alpelisib + nab-paclitaxel
    Number of subjects analysed
    35
    Units: months
        median (confidence interval 95%)
    3.71 (3.15 to 5.88)
    No statistical analyses for this end point

    Secondary: PFS Based on Local Radiology Assessments Using RECIST 1.1 Criteria for Participants by PIK3CA Mutation Status Measured in Baseline Circulating Tumor Deoxyribonucleic Acid (ctDNA) in Study Part A

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    End point title
    		 PFS Based on Local Radiology Assessments Using RECIST 1.1 Criteria for Participants by PIK3CA Mutation Status Measured in Baseline Circulating Tumor Deoxyribonucleic Acid (ctDNA) in Study Part A [20]
    End point description
    PFS in participants with PIK3CA mutation as measured in ctDNA. PFS was defined as time from the date of randomization to the date of the first documented progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
    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: Endpoint only applicable to Study Part A
    End point values
    		 Part A: alpelisib + nab-paclitaxel Part A: placebo + nab-paclitaxel
    Number of subjects analysed
    27
    22
    Units: months
        median (confidence interval 95%)
    7.5 (3.58 to 9.17)
    3.5 (1.77 to 5.85)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from first dose until 30 days after last dose, for up to 28 months (Part A: alpelisib+nab-paclitaxel), 58 months (Part A: placebo+nab-paclitaxel), and 31 months (Part B1: alpelisib+nab-paclitaxel).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo + Nab Part A
    Reporting group description
    		 Placebo + Nab Part A

    Reporting group title
    Alpelisib + Nab Part A
    Reporting group description
    		 Alpelisib + Nab Part A

    Reporting group title
    Alpelisib + Nab Part B1
    Reporting group description
    		 Alpelisib + Nab Part B1

    Serious adverse events
    		 Placebo + Nab Part A Alpelisib + Nab Part A Alpelisib + Nab Part B1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 50 (34.00%)
    24 / 52 (46.15%)
    14 / 35 (40.00%)
         number of deaths (all causes)
    6
    7
    3
         number of deaths resulting from adverse events
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Infected neoplasm
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Chills
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Peripheral swelling
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial fistula
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 52 (9.62%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    10 / 10
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Respiratory failure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Weight decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Headache
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
    0 / 35 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Diarrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess soft tissue
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    COVID-19
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Breast abscess
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    0 / 35 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    0 / 35 (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
    Hypernatraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         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
    		 Placebo + Nab Part A Alpelisib + Nab Part A Alpelisib + Nab Part B1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 50 (94.00%)
    51 / 52 (98.08%)
    35 / 35 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    4
    4
    6
    Lymphoedema
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    2
    4
    6
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    0 / 35 (0.00%)
         occurrences all number
    0
    6
    0
    Asthenia
         subjects affected / exposed
    5 / 50 (10.00%)
    9 / 52 (17.31%)
    4 / 35 (11.43%)
         occurrences all number
    12
    20
    10
    Fatigue
         subjects affected / exposed
    12 / 50 (24.00%)
    13 / 52 (25.00%)
    9 / 35 (25.71%)
         occurrences all number
    40
    32
    22
    Malaise
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    1 / 35 (2.86%)
         occurrences all number
    0
    6
    2
    Peripheral swelling
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 52 (5.77%)
    2 / 35 (5.71%)
         occurrences all number
    6
    6
    4
    Pain
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    4
    4
    4
    Oedema peripheral
         subjects affected / exposed
    9 / 50 (18.00%)
    4 / 52 (7.69%)
    5 / 35 (14.29%)
         occurrences all number
    22
    8
    16
    Mucosal inflammation
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 52 (9.62%)
    3 / 35 (8.57%)
         occurrences all number
    6
    14
    12
    Pyrexia
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 52 (15.38%)
    5 / 35 (14.29%)
         occurrences all number
    14
    20
    20
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    4
    0
    4
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 52 (5.77%)
    0 / 35 (0.00%)
         occurrences all number
    8
    6
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 50 (14.00%)
    9 / 52 (17.31%)
    5 / 35 (14.29%)
         occurrences all number
    24
    22
    10
    Dyspnoea
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 52 (9.62%)
    5 / 35 (14.29%)
         occurrences all number
    6
    14
    10
    Pleural effusion
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
    5 / 35 (14.29%)
         occurrences all number
    2
    4
    10
    Oropharyngeal pain
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    4
    6
    4
    Productive cough
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 52 (9.62%)
    1 / 35 (2.86%)
         occurrences all number
    2
    10
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    6
    0
    0
    Insomnia
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 52 (5.77%)
    2 / 35 (5.71%)
         occurrences all number
    14
    6
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 52 (13.46%)
    4 / 35 (11.43%)
         occurrences all number
    6
    24
    8
    Alpha hydroxybutyrate dehydrogenase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 52 (5.77%)
    3 / 35 (8.57%)
         occurrences all number
    6
    6
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 50 (16.00%)
    9 / 52 (17.31%)
    4 / 35 (11.43%)
         occurrences all number
    22
    30
    8
    Blood chloride decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    4
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
    4 / 35 (11.43%)
         occurrences all number
    0
    4
    10
    Blood insulin increased
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences all number
    8
    2
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 52 (7.69%)
    1 / 35 (2.86%)
         occurrences all number
    2
    20
    4
    Blood creatinine increased
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 52 (11.54%)
    4 / 35 (11.43%)
         occurrences all number
    4
    36
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 50 (18.00%)
    10 / 52 (19.23%)
    4 / 35 (11.43%)
         occurrences all number
    20
    22
    10
    Lipase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 52 (7.69%)
    1 / 35 (2.86%)
         occurrences all number
    0
    12
    2
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 52 (3.85%)
    1 / 35 (2.86%)
         occurrences all number
    38
    4
    2
    Neutrophil count decreased
         subjects affected / exposed
    12 / 50 (24.00%)
    11 / 52 (21.15%)
    3 / 35 (8.57%)
         occurrences all number
    114
    100
    32
    Platelet count decreased
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 52 (7.69%)
    2 / 35 (5.71%)
         occurrences all number
    28
    12
    6
    Weight decreased
         subjects affected / exposed
    6 / 50 (12.00%)
    25 / 52 (48.08%)
    14 / 35 (40.00%)
         occurrences all number
    12
    60
    28
    White blood cell count decreased
         subjects affected / exposed
    9 / 50 (18.00%)
    12 / 52 (23.08%)
    3 / 35 (8.57%)
         occurrences all number
    102
    108
    16
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    6
    0
    4
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    6
    0
    2
    Headache
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 52 (9.62%)
    5 / 35 (14.29%)
         occurrences all number
    10
    12
    10
    Dysgeusia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    2
    4
    4
    Dizziness
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 52 (7.69%)
    4 / 35 (11.43%)
         occurrences all number
    10
    8
    12
    Lethargy
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
    1 / 35 (2.86%)
         occurrences all number
    4
    6
    2
    Neuropathy peripheral
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 52 (9.62%)
    3 / 35 (8.57%)
         occurrences all number
    16
    10
    8
    Taste disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    2 / 35 (5.71%)
         occurrences all number
    0
    6
    4
    Polyneuropathy
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences all number
    8
    2
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 52 (5.77%)
    3 / 35 (8.57%)
         occurrences all number
    6
    6
    6
    Tremor
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    4
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 50 (46.00%)
    26 / 52 (50.00%)
    11 / 35 (31.43%)
         occurrences all number
    110
    98
    38
    Lymphopenia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
    3 / 35 (8.57%)
         occurrences all number
    22
    2
    8
    Leukopenia
         subjects affected / exposed
    7 / 50 (14.00%)
    11 / 52 (21.15%)
    4 / 35 (11.43%)
         occurrences all number
    56
    38
    12
    Leukocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    4
    Neutropenia
         subjects affected / exposed
    14 / 50 (28.00%)
    11 / 52 (21.15%)
    8 / 35 (22.86%)
         occurrences all number
    100
    46
    42
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    2
    6
    8
    Abdominal pain
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
    0 / 35 (0.00%)
         occurrences all number
    4
    6
    0
    Constipation
         subjects affected / exposed
    6 / 50 (12.00%)
    7 / 52 (13.46%)
    7 / 35 (20.00%)
         occurrences all number
    14
    14
    14
    Diarrhoea
         subjects affected / exposed
    12 / 50 (24.00%)
    33 / 52 (63.46%)
    21 / 35 (60.00%)
         occurrences all number
    36
    170
    80
    Haemorrhoids
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
    3 / 35 (8.57%)
         occurrences all number
    2
    2
    6
    Flatulence
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    4
    Dyspepsia
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
    5 / 35 (14.29%)
         occurrences all number
    6
    6
    10
    Nausea
         subjects affected / exposed
    12 / 50 (24.00%)
    21 / 52 (40.38%)
    17 / 35 (48.57%)
         occurrences all number
    30
    56
    50
    Stomatitis
         subjects affected / exposed
    2 / 50 (4.00%)
    13 / 52 (25.00%)
    7 / 35 (20.00%)
         occurrences all number
    6
    34
    24
    Vomiting
         subjects affected / exposed
    6 / 50 (12.00%)
    14 / 52 (26.92%)
    4 / 35 (11.43%)
         occurrences all number
    14
    36
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    16 / 50 (32.00%)
    13 / 52 (25.00%)
    8 / 35 (22.86%)
         occurrences all number
    32
    26
    16
    Dry skin
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 52 (7.69%)
    2 / 35 (5.71%)
         occurrences all number
    2
    8
    4
    Pruritus
         subjects affected / exposed
    6 / 50 (12.00%)
    6 / 52 (11.54%)
    5 / 35 (14.29%)
         occurrences all number
    18
    14
    12
    Rash
         subjects affected / exposed
    15 / 50 (30.00%)
    13 / 52 (25.00%)
    5 / 35 (14.29%)
         occurrences all number
    50
    30
    12
    Rash maculo-papular
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 52 (9.62%)
    2 / 35 (5.71%)
         occurrences all number
    0
    10
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences all number
    6
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 50 (18.00%)
    4 / 52 (7.69%)
    4 / 35 (11.43%)
         occurrences all number
    20
    10
    8
    Back pain
         subjects affected / exposed
    8 / 50 (16.00%)
    7 / 52 (13.46%)
    4 / 35 (11.43%)
         occurrences all number
    18
    16
    8
    Muscle spasms
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 52 (7.69%)
    1 / 35 (2.86%)
         occurrences all number
    2
    8
    2
    Muscular weakness
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
    2 / 35 (5.71%)
         occurrences all number
    6
    2
    6
    Myalgia
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 52 (3.85%)
    2 / 35 (5.71%)
         occurrences all number
    10
    4
    8
    Pain in extremity
         subjects affected / exposed
    8 / 50 (16.00%)
    3 / 52 (5.77%)
    1 / 35 (2.86%)
         occurrences all number
    18
    6
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    11 / 50 (22.00%)
    5 / 52 (9.62%)
    3 / 35 (8.57%)
         occurrences all number
    30
    12
    6
    Paronychia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    6
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 52 (9.62%)
    1 / 35 (2.86%)
         occurrences all number
    8
    10
    4
    Urinary tract infection
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 52 (7.69%)
    2 / 35 (5.71%)
         occurrences all number
    24
    10
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 50 (10.00%)
    14 / 52 (26.92%)
    8 / 35 (22.86%)
         occurrences all number
    12
    30
    18
    Diabetes mellitus
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    3 / 35 (8.57%)
         occurrences all number
    0
    2
    12
    Hyperglycaemia
         subjects affected / exposed
    8 / 50 (16.00%)
    38 / 52 (73.08%)
    19 / 35 (54.29%)
         occurrences all number
    32
    170
    54
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    4
    Hypocalcaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
    3 / 35 (8.57%)
         occurrences all number
    14
    10
    6
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 52 (3.85%)
    3 / 35 (8.57%)
         occurrences all number
    12
    4
    6
    Hyperuricaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
    1 / 35 (2.86%)
         occurrences all number
    14
    4
    4
    Hypokalaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    13 / 52 (25.00%)
    5 / 35 (14.29%)
         occurrences all number
    10
    44
    16
    Hyponatraemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
    3 / 35 (8.57%)
         occurrences all number
    8
    8
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 May 2021
    The main purposes of this amendment were to: ● incorporate guidance related to the use of SGLT2 inhibitors for the management of hyperglycemia, an on-target side effect of the PI3K inhibitor alpelisib, ● incorporate further guidance on alpelisib associated rash and its optimal management. ● implement a separate biomarker prescreening ICF to allow greater flexibility to investigators and sites in pre identifying potential study participants that meet the required biomarker profile. ● allow TNBC patients with tumor harboring PTEN loss and unknown PIK3CA status to enroll into study Part B1. In addition, language related to a Public Health emergency was added, wording was aligned to Novartis protocol template v4.0 language and clarifications and updates in response to health authority feedback were incorporated.
    14 Mar 2023
    The main purpose of this amendment was to modify the study conduct and data analysis following the recruitment halt on 11-Nov-2022 in Part A due to slow recruitment. Part B1 did not meet its primary objective for confirmed ORR. Therefore, Part B2 was not initiated, recruitment was halted for the entire study and the primary analysis for Part A was descriptive only. Ongoing participants were allowed to continue study treatment if they derived benefits as assessed by the investigator. Significant changes included: ● Adjustment of objectives and endpoints due to limited sample size in Part A (descriptive primary analysis, OS would be a secondary rather than a key secondary endpoint, PK, PROs, and time to deterioration of ECOG performance status were moved from secondary to exploratory endpoints). ● Allowed unblinding of all participants in Part A for investigators to know participant’s current treatment allocation. ● Safety and efficacy assessments once all participants had completed 6 months of study treatment or had discontinued from study treatment were streamlined. ● The protocol was updated based on the Investigator’s Brochure Edition 17.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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