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    Clinical Trial Results:
    A phase IIIb, open-label, local, multicenter study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2-negative advanced breast cancer on first-line treatment with ribociclib plus letrozole and, in patients with a PIK3CA mutation, on second-line treatment with alpelisib plus fulvestrant (BioItaLEE)

    Summary
    EudraCT number
    		 2017-004176-62
    Trial protocol
    		 IT  
    Global end of trial date
    11 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2024
    First version publication date
    22 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLEE011AIT01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03439046
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, 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
    11 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to identify circulating tumor DNA (ctDNA) alterations, how they evolve, and evaluate their possible association with clinical outcome in both first-line treatment with ribociclib and letrozole and second-line treatment with alpelisib and fulvestrant. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results.
    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
    02 Feb 2018
    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
    Italy: 287
    Worldwide total number of subjects
    287
    EEA total number of subjects
    287
    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)
    125
    From 65 to 84 years
    161
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All inclusion and exclusion criteria were checked at screening.

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Ribociclib+letrozole (Core Phase)
    Arm description
    		 Ribociclib oral (3 weeks on/1 week off) in combination with oral once daily letrozole: 600 mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib oral (3 weeks on/1 week off) in combination with oral once daily letrozole: 600 mg tablets ribociclib QD + 2.5 mg tablets letrozole QD

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    Other name
    LEE011
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib oral (3 weeks on/1 week off) in combination with oral once daily letrozole: 600 mg tablets ribociclib QD + 2.5 mg tablets letrozole QD

    Number of subjects in period 1
    		Ribociclib+letrozole (Core Phase)
    Started
    287
    Completed
    184
    Not completed
    103
         Adverse event, serious fatal
    27
         Other
    2
         Study terminated by sponsor
    45
         Lost to follow-up
    14
         Subject/guardian decision
    15
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Alpelisib+fulvestrant (Extension Phase)
    Arm description
    		 Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28-day 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
    Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28-day cycle

    Number of subjects in period 2 [1]
    		Alpelisib+fulvestrant (Extension Phase)
    Started
    21
    Completed
    16
    Not completed
    5
         Adverse event, serious fatal
    3
         Lost to follow-up
    1
         Subject/guardian decision
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: This arm included patients with PIK3CA mutations who entered the extension phase after treatment discontinuation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ribociclib+letrozole (Core Phase)
    Reporting group description
    		 Ribociclib oral (3 weeks on/1 week off) in combination with oral once daily letrozole: 600 mg tablets ribociclib QD + 2.5 mg tablets letrozole QD

    Reporting group values
    		 Ribociclib+letrozole (Core Phase) Total
    Number of subjects
    		 287 287
    Age Categorical
    Units: participants
        in utero
    		 0 0
        Preterm newborns infants
    		 0 0
        0 - <28 days
    		 0 0
        28 days - <2 years
    		 0 0
        2 years - <12 years
    		 0 0
        12 years - <18 years
    		 0 0
        18 years - <65 years
    		 125 125
        65 years - <85 years
    		 161 161
        >=85 years
    		 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.5 ( 8.39 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 287 287
        Male
    		 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 280 280
        Asian
    		 1 1
        Unknown Race
    		 5 5
        Other Race
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Ribociclib+letrozole (Core Phase)
    Reporting group description
    		 Ribociclib oral (3 weeks on/1 week off) in combination with oral once daily letrozole: 600 mg tablets ribociclib QD + 2.5 mg tablets letrozole QD
    Reporting group title
    Alpelisib+fulvestrant (Extension Phase)
    Reporting group description
    		 Alpelisib 300 mg oral daily on a continuous dosing schedule in combination with fulvestrant 500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each cycle thereafter in a 28-day cycle

    Primary: Number of Participants With Hotspot Mutated Genes by Scheduled Timepoint

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    End point title
    		 Number of Participants With Hotspot Mutated Genes by Scheduled Timepoint [1]
    End point description
    Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. The data row labels below refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease. EOT = end of treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 5.7 years
    Notes
    [1] - 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: Not applicable.
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    263
    Units: participants
        None at Screening n=263
    145
        None at Cycle 1 Day 15 n=238
    152
        None at Cycle 2 Day 1 n=242
    160
        None at First Imaging Evaluation n=206
    147
        None at EOT due to PD n=118
    50
        None at EOT due to Other n=39
    27
        1 at Screening n=263
    70
        1 at Cycle 1 Day 15 n=238
    51
        1 at Cycle 2 Day 1 n=242
    53
        1 at First Imaging Evaluation n=206
    40
        1 at EOT due to PD n=118
    26
        1 at EOT due to Other n=39
    10
        2 at Screening n=263
    32
        2 at Cycle 1 Day 15 n=238
    28
        2 at Cycle 2 Day 1 n=242
    21
        2 at First Imaging Evaluation n=206
    11
        2 at EOT due to PD n=118
    21
        2 at EOT due to Other n=39
    2
        3 or More at Screening n=263
    16
        3 or More at Cycle 1 Day 15 n=238
    7
        3 or More at Cycle 2 Day 1 n=242
    8
        3 or More at First Imaging Evaluation n=206
    8
        3 or More at EOT due to PD n=118
    21
        3 or More at EOT due to Other n=39
    0
    No statistical analyses for this end point

    Primary: Percent Change From Screening in Target Mutation Variant Allele Frequency (VAF)

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    End point title
    		 Percent Change From Screening in Target Mutation Variant Allele Frequency (VAF) [2]
    End point description
    The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.
    End point type
    Primary
    End point timeframe
    Up to approximately 5.7 years
    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: Not applicable.
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    263
    Units: percent change
    median (full range (min-max))
        Cycle 1, Day 15 n=104
    -94.33 (-100.0 to 134.5)
        Cycle 2, Day 1 n=106
    -100.00 (-100.0 to 167.8)
        First Imaging Evaluation n=90
    -100.00 (-100.0 to 1110.9)
        End of Treatment due to PD n=66
    -47.48 (-100.0 to 1133.9)
        End of treatment due to other n=16
    -100.00 (-100.0 to 29.8)
    No statistical analyses for this end point

    Primary: Number of Participants With Partial Response (PR) in the Extension Phase

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    End point title
    		 Number of Participants With Partial Response (PR) in the Extension Phase [3]
    End point description
    PR was assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1, criteria and was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the screening sum of diameters.
    End point type
    Primary
    End point timeframe
    Up to approximately 1.6 years
    Notes
    [3] - 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: Not applicable.
    End point values
    		 Alpelisib+fulvestrant (Extension Phase)
    Number of subjects analysed
    0 [4]
    Units: participants
    Notes
    [4] - This endpoint was not assessed.
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change

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    End point title
    		 Progression-Free Survival (PFS) by Cycle 1 Day 15 Complete Mutational Dynamic Change [5]
    End point description
    PFS: Time (months) from start of the study treatment to first documented progression or death due to any cause, whichever came first. Kaplan-Meier estimates. Persistent Wild Type: Wild Type (or single nucleotide polymorphisms [SNPs] only) at screening without hotspot mutations at any later assessment. Confirmed cleared: Mutated, with 100% decrease in target mutation variant allele frequency (VAF) at C1D15 or at C2D1 also observed at FI. Unconfirmed cleared: Mutated that cleared or at C1D15 or at C2D1 that were not cleared at FI. Late cleared: Mutated without 100% decrease in target mutation VAF at C1D15 and at C2D1 with 100% decrease in target mutation VAF at FI. New mutated: Wild Type ( [SNPs] only) at screening with hotspot mutations at C1D15 or C2D1. Late mutated: Wild Type patients (or SNPs only) at screening without hotspot mutations at C1D15 and C2D1 with hotspot mutations at FI. Confirmed mutated: Mutated without 100% decrease in target mutation VAF at any later assessment.
    End point type
    Primary
    End point timeframe
    Up to approximately 5.7 years
    Notes
    [5] - 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: Not applicable.
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    187
    Units: months
    median (confidence interval 95%)
        Persistent Wild Type n=76
    55.82 (39.06 to 999)
        New Mutated n=19
    16.53 (9.03 to 45.90)
        Late Mutated n=8
    15.67 (2.00 to 21.42)
        Confirmed Cleared n=46
    22.44 (15.93 to 32.23)
        Unconfirmed Cleared n=8
    10.22 (2.69 to 999)
        Late Cleared n=12
    11.07 (3.29 to 19.09)
        Confirmed Mutated n=18
    14.32 (2.89 to 44.22)
    No statistical analyses for this end point

    Primary: Number of Participants With Progression-Free Survival (PFS) Events by Cycle 1 Day 15 Complete Mutational Dynamic Change

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    End point title
    		 Number of Participants With Progression-Free Survival (PFS) Events by Cycle 1 Day 15 Complete Mutational Dynamic Change [6]
    End point description
    Kaplan-Meier estimates. Persistent Wild Type: Wild Type (or single nucleotide polymorphisms [SNPs] only) at screening without hotspot mutations at any later assessment. Confirmed cleared: Mutated, with 100% decrease in target mutation variant allele frequency (VAF) at C1D15 or at C2D1 also observed at FI. Unconfirmed cleared: Mutated that cleared or at C1D15 or at C2D1 that were not cleared at FI. Late cleared: Mutated without 100% decrease in target mutation VAF at C1D15 and at C2D1 with 100% decrease in target mutation VAF at FI. New mutated: Wild Type ( [SNPs] only) at screening with hotspot mutations at C1D15 or C2D1. Late mutated: Wild Type patients (or SNPs only) at screening without hotspot mutations at C1D15 and C2D1 with hotspot mutations at FI. Confirmed mutated: Mutated without 100% decrease in target mutation VAF at any later assessment.
    End point type
    Primary
    End point timeframe
    Up to approximately 5.7 years
    Notes
    [6] - 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: Not applicable.
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    187
    Units: participants
        Persistent Wild Type n=76
    31
        New Mutated n=19
    13
        Late Mutated n=8
    6
        Confirmed Cleared n=46
    28
        Unconfirmed Cleared n=8
    6
        Late Cleared n=12
    10
        Confirmed Mutated n=18
    12
    No statistical analyses for this end point

    Secondary: Percent Change From Screening in Thymidine Kinase 1 (TK1) Serum Level

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    End point title
    		 Percent Change From Screening in Thymidine Kinase 1 (TK1) Serum Level
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    263
    Units: percent change
    median (full range (min-max))
        Cycle 1, Day 15 n=245
    -73.2 (-99 to 2370)
        Cycle 2, Day 1 n=241
    -39.3 (-96 to 1378)
        First Imaging Evaluation n=208
    -46.9 (-99 to 1604)
        End of Treatment due to PD n=89
    56.5 (-98 to 10033)
        End of treatment due to other n=35
    28.5 (-92 to 109213)
    No statistical analyses for this end point

    Secondary: Number of Long Responder Participants With Hotspot Mutated Genes by Scheduled Timepoint

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    End point title
    		 Number of Long Responder Participants With Hotspot Mutated Genes by Scheduled Timepoint
    End point description
    Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    116
    Units: participants
        None at Screening n=95
    64
        None at Cycle 1 Day 15 n=84
    60
        None at Cycle 2, Day 1 n=91
    67
        None at First Imaging Evaluation n=82
    66
        None at EOT due to PD n=27
    14
        None at EOT due to Other n=4
    1
        1 at Screening n=95
    23
        1 at Cycle 1 Day 15 n=84
    18
        1 at Cycle 2, Day 1 n=91
    22
        1 at First Imaging Evaluation n=82
    14
        1 at EOT due to PD n=27
    7
        1 at EOT due to Other n=4
    3
        2 at Screening n=95
    4
        2 at Cycle 1 Day 15 n=84
    4
        2 at Cycle 2, Day 1 n=91
    2
        2 at First Imaging Evaluation n=82
    2
        2 at EOT due to PD n=27
    2
        2 at EOT due to Other n=4
    0
        3 or More at Screening n=95
    4
        3 or More at Cycle 1 Day 15 n=84
    2
        3 or More at Cycle 2, Day 1 n=91
    0
        3 or More at First Imaging Evaluation n=82
    0
        3 or More at EOT due to PD n=27
    4
        3 or More at EOT due to Other n=4
    0
    No statistical analyses for this end point

    Secondary: Number of Early Progressor Participants With Hotspot Mutated Genes by Scheduled Timepoint

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    End point title
    		 Number of Early Progressor Participants With Hotspot Mutated Genes by Scheduled Timepoint
    End point description
    Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    116
    Units: participants
        None at Screening n=21
    8
        None at Cycle 1 Day 15 n=19
    7
        None at Cycle 2, Day 1 n=21
    9
        None at First Imaging Evaluation n=19
    9
        None at EOT due to PD n=20
    7
        None at EOT due to Other n=0
    999
        1 at Screening n=21
    5
        1 at Cycle 1 Day 15 n=19
    3
        1 at Cycle 2, Day 1 n=21
    3
        1 at First Imaging Evaluation n=19
    3
        1 at EOT due to PD n=20
    4
        1 at EOT due to Other n=0
    999
        2 at Screening n=21
    5
        2 at Cycle 1 Day 15 n=19
    8
        2 at Cycle 2, Day 1 n=21
    5
        2 at First Imaging Evaluation n=19
    5
        2 at EOT due to PD n=20
    5
        2 at EOT due to Other n=0
    999
        3 or More at Screening n=21
    3
        3 or More at Cycle 1 Day 15 n=19
    1
        3 or More at Cycle 2, Day 1 n=21
    4
        3 or More at First Imaging Evaluation n=19
    2
        3 or More at EOT due to PD n=20
    4
        3 or More at EOT due to Other n=0
    999
    No statistical analyses for this end point

    Secondary: Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Long Responders

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    End point title
    		 Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Long Responders
    End point description
    The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    28
    Units: percent change
    median (full range (min-max))
        Cycle 1, Day 15 n=26
    -98.82 (-100.0 to 101.6)
        Cycle 2, Day 1 n=27
    -100.00 (-100.0 to 88.8)
        First Imaging Evaluation n=23
    -100.00 (-100.0 to 40.5)
        End of Treatment due to PD n=12
    -52.93 (-100.0 to 319.7)
        End of treatment due to other n=2
    -35.12 (-100.0 to 29.8)
    No statistical analyses for this end point

    Secondary: Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Early Progressors

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    End point title
    		 Percent Change From Screening in Target Mutation Molecular Frequency (VAF) for Early Progressors
    End point description
    The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    13
    Units: percent change
    median (full range (min-max))
        Cycle 1, Day 15 n=12
    -42.45 (-100.0 to 77.5)
        Cycle 2, Day 1 n=13
    -70.05 (-100.0 to 37.9)
        First Imaging Evaluation n=11
    -56.76 (-100.0 to 1110.9)
        End of Treatment due to PD n=12
    -24.31 (-100.0 to 707.2)
    No statistical analyses for this end point

    Secondary: Number of Screening Hotspot Mutations per De Novo Patient in Liquid Biopsy Samples and Tissue Samples

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    End point title
    		 Number of Screening Hotspot Mutations per De Novo Patient in Liquid Biopsy Samples and Tissue Samples
    End point description
    Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    105
    Units: participants
        None (Valid Liquid Biopsy Sample) n=105
    59
        One (Valid Liquid Biopsy Sample) n=105
    31
        Two (Valid Liquid Biopsy Sample) n=105
    11
        Three or More (Valid Liquid Biopsy Sample) n=105
    4
        None (Valid Tissue Sample) n=72
    23
        One (Valid Tissue Sample) n=72
    26
        Two (Valid Tissue Sample) n=72
    17
        Three or More (Valid Tissue Sample) n=72
    6
    No statistical analyses for this end point

    Secondary: Number of Screening Hotspot Mutations per Recurrent Patient in Liquid Biopsy Samples and Tissue Samples

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    End point title
    		 Number of Screening Hotspot Mutations per Recurrent Patient in Liquid Biopsy Samples and Tissue Samples
    End point description
    Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    158
    Units: participants
        None (Valid Liquid Biopsy Sample) n=158
    86
        One (Valid Liquid Biopsy Sample) n=158
    39
        Two (Valid Liquid Biopsy Sample) n=158
    21
        Three or More (Valid Liquid Biopsy Sample) n=158
    12
        None (Valid Tissue Sample) n=67
    15
        One (Valid Tissue Sample) n=67
    25
        Two (Valid Tissue Sample) n=67
    13
        Three or More (Valid Tissue Sample) n=67
    14
    No statistical analyses for this end point

    Secondary: Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at Screening

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    End point title
    		 Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at Screening
    End point description
    Results data refer to the total number of evaluations (i.e. the number of participants in the biomarker analysis set with both valid baseline liquid biopsy and tissue sample multiplied by 39 considered genes). HM = hotspot-mutated.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    263
    Units: evaluations
        Liquid Biopsy HM, Tissue Sample HM
    68
        Liquid Biopsy HM, Tissue Sample Not HM
    27
        Liquid Biopsy Not HM, Tissue Sample HM
    99
        Liquid Biopsy Not HM, Tissue Sample Not HM
    5227
    No statistical analyses for this end point

    Secondary: Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at End of Treatment

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    End point title
    		 Overall Number of Evaluations of Hotspot Mutations and Non-hotspot Mutations Present in Both Liquid Biopsies and Tissue Samples at End of Treatment
    End point description
    Results data refer to the total number of evaluations (i.e. the number of participants in the biomarker analysis set with both valid baseline liquid biopsy and tissue sample multiplied by 39 considered genes). HM = hotspot-mutated.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    263
    Units: evaluations
        Liquid Biopsy HM, Tissue Sample HM
    5
        Liquid Biopsy HM, Tissue Sample Not HM
    1
        Liquid Biopsy Not HM, Tissue Sample HM
    0
        Liquid Biopsy Not HM, Tissue Sample Not HM
    150
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to progression (TTP) was defined as time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer.
    End point type
    Secondary
    End point timeframe
    Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    263
    Units: months
        median (confidence interval 95%)
    30.42 (21.42 to 40.41)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Best Overall Response Rate of Complete Response (CR) or Partial Response (PR)

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    End point title
    		 Percentage of Participants With Best Overall Response Rate of Complete Response (CR) or Partial Response (PR)
    End point description
    ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 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 diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    236
    Units: percentage of participants
        median (confidence interval 95%)
    38.56 (32.32 to 45.09)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Benefit Rate

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    End point title
    		 Percentage of Participants With Clinical Benefit Rate
    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. Per RECIST v. 1.1, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.
    End point type
    Secondary
    End point timeframe
    Core phase: up to approximately 5.7 years. Extension phase: up to approximately 1.6 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    236
    Units: percentage of participants
        number (confidence interval 95%)
    73.31 (67.18 to 78.84)
    No statistical analyses for this end point

    Secondary: Change From Baseline Tumor Mutational Burden (TMB) to Progression of Disease During the Core and Extension Phases

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    End point title
    		 Change From Baseline Tumor Mutational Burden (TMB) to Progression of Disease During the Core and Extension Phases
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    0 [7]
    Units: Not applicable
        number (not applicable)
    Notes
    [7] - This endpoint was not assessed.
    No statistical analyses for this end point

    Secondary: Change From Baseline Tumor Microenvironment Parameters to Progression of Disease During the Core and Extension Phases

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    End point title
    		 Change From Baseline Tumor Microenvironment Parameters to Progression of Disease During the Core and Extension Phases
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.7 years
    End point values
    		 Ribociclib+letrozole (Core Phase)
    Number of subjects analysed
    0 [8]
    Units: Not applicable
        number (not applicable)
    Notes
    [8] - This endpoint was not assessed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Extension Phase
    Reporting group description
    		 Extension Phase

    Reporting group title
    Core Phase
    Reporting group description
    		 Core Phase

    Serious adverse events
    		 Extension Phase Core Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    79 / 287 (27.53%)
         number of deaths (all causes)
    3
    27
         number of deaths resulting from adverse events
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Endocrine hypertension
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sudden death
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 21 (0.00%)
    7 / 287 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product dispensing error
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Tremor
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hemiparesis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aphasia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Lens dislocation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Extension Phase Core Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 21 (95.24%)
    275 / 287 (95.82%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
    58 / 287 (20.21%)
         occurrences all number
    3
    144
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
    53 / 287 (18.47%)
         occurrences all number
    4
    115
    Blood creatinine increased
         subjects affected / exposed
    3 / 21 (14.29%)
    28 / 287 (9.76%)
         occurrences all number
    4
    83
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    13 / 287 (4.53%)
         occurrences all number
    2
    22
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 21 (0.00%)
    18 / 287 (6.27%)
         occurrences all number
    0
    21
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    0
    28
    Neutrophil count decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    56 / 287 (19.51%)
         occurrences all number
    0
    435
    Platelet count decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    30 / 287 (10.45%)
         occurrences all number
    0
    68
    Weight decreased
         subjects affected / exposed
    5 / 21 (23.81%)
    6 / 287 (2.09%)
         occurrences all number
    5
    6
    White blood cell count decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    61 / 287 (21.25%)
         occurrences all number
    0
    222
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
    16 / 287 (5.57%)
         occurrences all number
    1
    28
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 21 (9.52%)
    11 / 287 (3.83%)
         occurrences all number
    2
    14
    Headache
         subjects affected / exposed
    1 / 21 (4.76%)
    21 / 287 (7.32%)
         occurrences all number
    1
    33
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    32 / 287 (11.15%)
         occurrences all number
    0
    109
    Neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    198 / 287 (68.99%)
         occurrences all number
    0
    1914
    Anaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    105 / 287 (36.59%)
         occurrences all number
    2
    327
    Leukopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    93 / 287 (32.40%)
         occurrences all number
    0
    830
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 287 (1.39%)
         occurrences all number
    2
    4
    Pyrexia
         subjects affected / exposed
    4 / 21 (19.05%)
    56 / 287 (19.51%)
         occurrences all number
    4
    78
    Oedema peripheral
         subjects affected / exposed
    2 / 21 (9.52%)
    14 / 287 (4.88%)
         occurrences all number
    2
    17
    Mucosal inflammation
         subjects affected / exposed
    5 / 21 (23.81%)
    16 / 287 (5.57%)
         occurrences all number
    8
    24
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    28 / 287 (9.76%)
         occurrences all number
    0
    51
    Chest pain
         subjects affected / exposed
    2 / 21 (9.52%)
    8 / 287 (2.79%)
         occurrences all number
    2
    9
    Asthenia
         subjects affected / exposed
    8 / 21 (38.10%)
    89 / 287 (31.01%)
         occurrences all number
    11
    174
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 21 (57.14%)
    56 / 287 (19.51%)
         occurrences all number
    23
    99
    Constipation
         subjects affected / exposed
    1 / 21 (4.76%)
    27 / 287 (9.41%)
         occurrences all number
    1
    30
    Abdominal pain upper
         subjects affected / exposed
    1 / 21 (4.76%)
    16 / 287 (5.57%)
         occurrences all number
    1
    24
    Abdominal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    20 / 287 (6.97%)
         occurrences all number
    1
    23
    Stomatitis
         subjects affected / exposed
    3 / 21 (14.29%)
    9 / 287 (3.14%)
         occurrences all number
    3
    10
    Nausea
         subjects affected / exposed
    7 / 21 (33.33%)
    95 / 287 (33.10%)
         occurrences all number
    8
    162
    Vomiting
         subjects affected / exposed
    3 / 21 (14.29%)
    47 / 287 (16.38%)
         occurrences all number
    4
    68
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 287 (0.70%)
         occurrences all number
    2
    2
    Cough
         subjects affected / exposed
    1 / 21 (4.76%)
    42 / 287 (14.63%)
         occurrences all number
    1
    57
    Dyspnoea
         subjects affected / exposed
    2 / 21 (9.52%)
    23 / 287 (8.01%)
         occurrences all number
    2
    30
    Pleural effusion
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 287 (0.35%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 21 (4.76%)
    27 / 287 (9.41%)
         occurrences all number
    1
    31
    Rash
         subjects affected / exposed
    8 / 21 (38.10%)
    32 / 287 (11.15%)
         occurrences all number
    10
    55
    Pruritus
         subjects affected / exposed
    3 / 21 (14.29%)
    47 / 287 (16.38%)
         occurrences all number
    3
    72
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 21 (4.76%)
    56 / 287 (19.51%)
         occurrences all number
    1
    87
    Back pain
         subjects affected / exposed
    2 / 21 (9.52%)
    27 / 287 (9.41%)
         occurrences all number
    2
    34
    Bone pain
         subjects affected / exposed
    1 / 21 (4.76%)
    28 / 287 (9.76%)
         occurrences all number
    1
    34
    Groin pain
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 287 (0.35%)
         occurrences all number
    2
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 21 (9.52%)
    11 / 287 (3.83%)
         occurrences all number
    2
    14
    Pain in extremity
         subjects affected / exposed
    0 / 21 (0.00%)
    15 / 287 (5.23%)
         occurrences all number
    0
    21
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 21 (4.76%)
    16 / 287 (5.57%)
         occurrences all number
    1
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 21 (14.29%)
    23 / 287 (8.01%)
         occurrences all number
    4
    31
    Hyperglycaemia
         subjects affected / exposed
    14 / 21 (66.67%)
    11 / 287 (3.83%)
         occurrences all number
    22
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2018
    This amendment: updated number of patients, timing of interim analysis, definition of end of study (EOS); clarified the inclusion and exclusion criteria and updated the definition of patient population; updated the management of treatment cycles in case of drug interruption and timelines or frequency of some trial assessments; updated and clarified biological sample collection timelines and assessments; updated definition of biomarker analysis set (BAS) and timing of interim analysis; added the updated references.
    28 May 2019
    This amendment: updated the background and rationale; updated study design, treatment, visit schedule, and safety information with alpelisib for the Extension Phase; added the statistical methods and data analysis for the Extension Phase; added the updated references; added the guidelines for alpelisib treatment.
    11 Dec 2019
    This amendment: updated clinical experience and approval information of alpelisib; added SOLAR-1 pharmacokinetic analyses and data on food effect; updated the inclusion /exclusion criteria based on alpelisib IB edition 13; updated additional guidance on missed dose instructions and follow-up on potential drug-induced liver injury (DILI); updated guidance on dose interruption/modifications, management of adverse events (AEs) associated with the use of alpelisib, and guidance for follow-up on toxicities; added general information on managing concomitant medications; updated permitted concomitant medications to be used with caution, prohibited medications, and the use of bisphosphonates/ denosumab based on updated information in relation to alpelisib; updated the list of medications according to amendment.
    19 Apr 2023
    This amendment: defined the procedure for study exit and established the possible post-trial access for alpelisib; changed detail in study procedure related to the final study visit and introduced the mechanism to ensure therapeutic continuity.

    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.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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