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    Clinical Trial Results:
    An Open-label Randomised Phase 2 Trial of Amcenestrant (SAR439859), Versus Endocrine Monotherapy as per Physician’s Choice in Patients With Estrogen Receptor-positive, HER2-negative Locally advanced or Metastatic breast cancer With Prior exposure to Hormonal Therapies

    Summary
    EudraCT number
    		 2018-004593-98
    Trial protocol
    		 SE   PL   ES   GR   CZ   LV   IT  
    Global end of trial date
    02 Jan 2025

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Jan 2026
    First version publication date
    15 Apr 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT16105
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04059484
    WHO universal trial number (UTN)
    		 U1111-1217-2774
    Other trial identifiers
    		 IND: 133204
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 Avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    16 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2025
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether amcenestrant 400 milligrams (mg) per os improves progression-free survival (PFS) when compared with an endocrine monotherapy of the choice of the physician, in participants with metastatic or locally advanced breast cancer.
    Protection of trial subjects
    Participants were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trial, participants were provided with individual participant cards indicating the nature of the trial the participant is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Oct 2019
    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
    Brazil: 22
    Country: Number of subjects enrolled
    Argentina: 25
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    China: 90
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 20
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    Türkiye: 13
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Latvia: 4
    Worldwide total number of subjects
    367
    EEA total number of subjects
    71
    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)
    251
    From 65 to 84 years
    115
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 367 participants were screened in main (global) cohort,77 were screen failures (not meeting eligibility criteria). As pre-specified in protocol, Chinese participants from main cohort and China cohort were pooled for purpose of analysis of Chinese cohort. 90 participants (including 13 participants from main cohort) were randomized in Chinese cohort.

    Pre-assignment
    Screening details
    		 Total 367 unique participants enrolled:290 participants (main cohort), 77 new participants (Chinese cohort). Study was terminated as it did not meet primary objective of improved progression free survival with amcenestrant versus endocrine treatment of physician's choice.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort
    Arm description
    		 Participants received potential control treatment of the choice of the physician depending on each participant’s medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-milliliters (mL) intramuscular (IM) injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg) orally (PO), once a day (QD); or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum exposure: 116 weeks).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Faslodex®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant 500 mg given as two 250 mg (5 mL) IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter.

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Nolvadex®/Tamoxifen Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tamoxifen 20 mg PO QD or 10 mg twice a day PO, approximately at the same time every day regardless of food status.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasin®/Exemestane Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg PO, QD approximately at the same time every day after a meal.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Arimidex®/Anastrozole Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole 1 mg PO, QD approximately at the same time every day regardless of food status.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Femara®/Letrozole Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole 2.5 mg PO, QD approximately at the same time every day regardless of food status.

    Arm title
    		 Amcenestrant- Main Cohort
    Arm description
    		 Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant’s request to stop treatment or Investigator decision, whichever occurred first (maximum exposure: 116 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amcenestrant
    Investigational medicinal product code
    SAR439859
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Amcenestrant (4 capsules of 100 mg) PO, QD from Day 1 to Day 28 in each 28-day treatment cycle in the morning with or without food, at approximately the same time every day.

    Arm title
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort
    Arm description
    		 Participants received potential control treatment of the choice of the physician depending on each participant's medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-mL IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg) PO, QD; or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum treatment exposure: 183 weeks).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Faslodex®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant 500 mg given as two 250 mg (5 mL) IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Arimidex®/Anastrozole Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole 1 mg PO, QD approximately at the same time every day regardless of food status.

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Nolvadex®/Tamoxifen Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tamoxifen 20 mg PO QD or 10 mg twice a day PO, approximately at the same time every day regardless of food status.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasin®/Exemestane Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg PO, QD approximately at the same time every day after a meal.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Femara®/Letrozole Generics
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole 2.5 mg PO, QD approximately at the same time every day regardless of food status.

    Arm title
    		 Amcenestrant- Chinese Cohort
    Arm description
    		 Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant's request to stop treatment or Investigator decision, whichever occurred first (maximum treatment exposure: 183 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amcenestrant
    Investigational medicinal product code
    SAR439859
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Amcenestrant (4 capsules of 100 mg) PO, QD from Day 1 to Day 28 in each 28-day treatment cycle in the morning with or without food, at approximately the same time every day.

    Number of subjects in period 1
    		Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Started
    147
    143
    42
    48
    Completed
    0
    0
    0
    0
    Not completed
    147
    143
    42
    48
         Consent withdrawn by subject
    6
    3
    1
    4
         Adverse event, non-fatal
    2
    5
    -
    1
         Not related to Coronavirus Disease-2019 (COVID-19)
    19
    17
    7
    10
         Related to COVID-19
    -
    -
    -
    1
         Poor compliance to protocol
    -
    -
    1
    -
         Progressive disease
    120
    118
    33
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 All participants in the study were included in this arm.

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 367
    Age categorical
    Units: participants
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.7 ( 12.1 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 365 365
        Male
    		 2 2
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 143 143
        Native Hawaiian or Other Pacific Islander
    		 2 2
        Black or African American
    		 0 0
        White
    		 204 204
        More than one race
    		 2 2
        Unknown or Not Reported
    		 16 16

    End points

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    End points reporting groups
    Reporting group title
    Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort
    Reporting group description
    		 Participants received potential control treatment of the choice of the physician depending on each participant’s medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-milliliters (mL) intramuscular (IM) injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg) orally (PO), once a day (QD); or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum exposure: 116 weeks).

    Reporting group title
    Amcenestrant- Main Cohort
    Reporting group description
    		 Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant’s request to stop treatment or Investigator decision, whichever occurred first (maximum exposure: 116 weeks).

    Reporting group title
    Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort
    Reporting group description
    		 Participants received potential control treatment of the choice of the physician depending on each participant's medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-mL IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg) PO, QD; or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum treatment exposure: 183 weeks).

    Reporting group title
    Amcenestrant- Chinese Cohort
    Reporting group description
    		 Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant's request to stop treatment or Investigator decision, whichever occurred first (maximum treatment exposure: 183 weeks).

    Primary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS) [1]
    End point description
    PFS is defined as the time in months interval from the date of randomization to the date of first documented tumor progression as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) assessed by independent central review (ICR) or death (due to any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. Analysis was performed on the ITT population which consist of all participants from the enrolled population (with a signed informed consent form) who have been allocated a randomization number by the Interactive Response Technology (IRT).
    End point type
    Primary
    End point timeframe
    From randomization to the date of first documented tumor progression or death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: months
        median (confidence interval 95%)
    3.7 (2.0 to 4.9)
    3.6 (2.0 to 3.9)
    Statistical analysis title
    		 Statistical Analysis for Progression Free Survival
    Statistical analysis description
    A hierarchical testing procedure was used to ensure a strong control of the overall Type I error. Testing was then performed sequentially in order the outcome measures was reported and continued when previous outcome measure was statistically significant at one-sided 2.5% for the primary and the first secondary outcome. Here, ECOG=Eastern Cooperative Oncology Group.
    Comparison groups
    Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort v Amcenestrant- Main Cohort
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6437 [2]
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.789
         upper limit
    		 1.4
    Notes
    [2] - One-sided p-value based on Stratified log-rank test. Threshold for statistical significance at 0.025. Stratified on presence of visceral metastasis, prior treatment with cyclin-dependent kinase 4/6 inhibitors and ECOG according to IRT.

    Primary: Chinese Cohort: Progression Free Survival

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    End point title
    		 Chinese Cohort: Progression Free Survival [3] [4]
    End point description
    PFS is defined as the time in months interval from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by ICR or death (due to any cause), whichever comes first. PD as per RECIST 1.1: at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. Analysis was performed on the ITT population. Here, '99999' is used as a space filler and denotes that median and upper limit of 95% confidence interval (CI) were not estimable due to insufficient number of participants with events at study termination.
    End point type
    Primary
    End point timeframe
    From randomization to the date of first documented tumor progression or death due to any cause or data cut-off date whichever comes first, up to primary completion date of 15-Feb-2022, a maximum of 121 weeks
    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: As the endpoint was descriptive in nature, no statistical analysis is reported.
    [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: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    42
    48
    Units: months
        median (confidence interval 95%)
    99999 (3.7 to 99999)
    7.2 (3.7 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [5]
    End point description
    OS is defined as the time interval from the date of randomization to the date of documented death (due to any cause). In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. Analysis was performed on the ITT population. Here, '99999' is used as a space filler and denotes that median and upper limit of 95% CI were not estimable due to the smaller number of participants with events.
    End point type
    Secondary
    End point timeframe
    From randomization to the death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: months
        median (confidence interval 95%)
    99999 (18.9 to 99999)
    99999 (21.5 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response

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    End point title
    		 Percentage of Participants With Objective Response [6]
    End point description
    Objective response is defined as percentage of participants having a partial response (PR) or complete response (CR) according to the RECIST version 1.1 assessed by ICR. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: percentage of participants
        number (confidence interval 95%)
    8.8 (4.8 to 14.6)
    11.9 (7.1 to 18.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Control

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    End point title
    		 Percentage of Participants With Disease Control [7]
    End point description
    Disease control is defined as percentage of participants having a confirmed CR, PR, or stable disease (SD) or Non-CR/Non-PD as BOR determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: percentage of participants
        number (confidence interval 95%)
    53.7 (45.3 to 62.0)
    54.5 (46.0 to 62.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Benefit

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    End point title
    		 Percentage of Participants With Clinical Benefit [8]
    End point description
    Clinical Benefit is defined as percentage of participants having a confirmed CR, PR, SD, or Non-CR/Non-PD for at least 24 weeks determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD:at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: percentage of participants
        number (confidence interval 95%)
    29.3 (22.0 to 37.3)
    27.3 (20.2 to 35.3)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status

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    End point title
    		 Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status [9]
    End point description
    PFS:time(in months) from randomization to date of first documented tumor progression per RECIST 1.1 assessed by ICR or death(due to any cause), whichever comes first.Progression as per RECIST 1.1:at least a 20 percent (%) increase in sum of diameters of target lesions,unequivocal progression of existing non-target lesions.Mutation status(wild type, mutant) of twelve specific mutations of ESR1 gene was determined by multiplex droplet digital polymerase chain reaction (ddPCR), including their mutant frequency and concentration. PFS is reported based on ESR1 mutation status of participants:wild type and mutants.ESR1:gene encoding estrogen receptor alpha.ESR1 mutant type breast cancer:disease where ESR1 gene had a mutation(i.e., type of error). ESR1 wild type breast cancer:disease where ESR1 gene was normal without mutation. Kaplan-Meier method. ITT population.'Number of subjects analyzed' & 'n' = participants with available data for this endpoint & each specified category, respectively.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    140
    140
    Units: months
    median (confidence interval 95%)
        Mutated (n = 55, 65)
    2.0 (1.9 to 4.3)
    3.7 (1.9 to 7.2)
        Wild type (n = 85, 75)
    3.9 (3.6 to 9.2)
    3.5 (2.0 to 3.7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR) [10]
    End point description
    DOR:time(in months) from first documented evidence of CR or PR until progressive disease(PD)determined by ICR as per RECIST 1.1 or death from any cause, whichever occurs first.For participants with ongoing response at time of analysis,DOR was censored at date of last valid disease assessment not showing documented progression performed before the initiation of a new anticancer treatment(if any).As per RECIST 1.1,CR:disappearance of all target and non-target lesions and normalization of tumor marker level.Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm.PR:at least a 30% decrease in the sum of diameters of target lesions, taking as reference baseline sum diameters.PD:at least 20% increase in sum of diameters of target lesions,unequivocal progression of existing non-target lesions.Analyzed on subset of participants with objective response.99999:median & 95% CI upper limit not estimable due to less number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of first response to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
    Notes
    [10] - 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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    13
    17
    Units: months
        median (confidence interval 95%)
    99999 (3.9 to 99999)
    15.1 (5.6 to 99999)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Plasma Concentrations of Amcenestrant

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    End point title
    		 Pharmacokinetics: Plasma Concentrations of Amcenestrant [11]
    End point description
    Amcenestrant plasma concentrations at specified time points are reported. Analysis was performed on pharmacokinetic-evaluable population: all participants who were assigned to study intervention, took at least 1 dose of study intervention and had at least 1 available plasma concentration post treatment with adequate documentation of date and time of dosing and date and time of sampling. Here, ‘n’ = participants with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 1.5 hours(h), 4h post-dose, Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 1.5h, 4h, 8h post-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 6 Day 1: pre-dose
    Notes
    [11] - 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: Data for this endpoint was not planned to be collected and analyzed for PCEM arm.
    End point values
    		 Amcenestrant- Main Cohort
    Number of subjects analysed
    140
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 1.5h (n = 130)
    3185.7 ( 3145.2 )
        Cycle 1 Day 1: 4h (n = 128)
    4753.1 ( 3463.7 )
        Cycle 1 Day 15: Pre-dose (n = 87)
    516.4 ( 377.2 )
        Cycle 2 Day 1: Pre-dose (n = 98)
    479.1 ( 320.3 )
        Cycle 2 Day 1: 1.5h (n = 121)
    2719.6 ( 2374.0 )
        Cycle 2 Day 1: 4h (n = 115)
    3801.8 ( 2370.8 )
        Cycle 2 Day 1: 8h (n = 98)
    2303.8 ( 1411.4 )
        Cycle 3 Day 1: Pre-dose (n = 42)
    593.6 ( 815.1 )
        Cycle 4 Day 1: Pre-dose (n = 44)
    661.5 ( 860.5 )
        Cycle 6 Day 1: Pre-dose (n = 28)
    531.5 ( 468.5 )
    No statistical analyses for this end point

    Secondary: Within-Participant Steady State Ctrough of Amcenestrant

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    End point title
    		 Within-Participant Steady State Ctrough of Amcenestrant [12]
    End point description
    Within-participant Steady state Ctrough was defined as the median value of the Ctrough across study using plasma concentration of predose samples at Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 for each individual participant. Average (mean) of all calculated Ctrough values for all participants across study (Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 ) was derived and reported in this outcome measure. Analysis was performed on Pharmacokinetic-evaluable population. Here, ‘number of subjects analyzed’ = participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Predose on Cycle 1 Day 15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 4 Day 1; Cycle 6 Day 1
    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: Data for this endpoint was not planned to be collected and analyzed for PCEM arm.
    End point values
    		 Amcenestrant- Main Cohort
    Number of subjects analysed
    123
    Units: ng/mL
        arithmetic mean (standard deviation)
    491.35 ( 316.51 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores [13]
    End point description
    Cancer-specific instrument with 30 questions for evaluation of new chemotherapy & assessment of participant reported outcome, includes 5 functional scales,9 symptom scales,& Global Health Status/quality of life scale (GHS/QoL).All 14 items/domains scored on scale of 1(not at all) to 4(very much) & GHS/QoL,scored on scale of 1(very poor) to 7(excellent).All scales are transformed from raw scores to linear scales ranging 0 to 100.Higher score for functional & GHS/QoL=higher level of functioning, & higher score for symptoms scales=higher symptom burden. Least Square(LS) mean and Standard Error(SE) are derived from MMRM model with change from Baseline values as response variable,treatment, time,treatment-by-time interaction,Baseline value and stratifications factors as fixed effect.Average of LS mean change from baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 30]). Safety population evaluable. ‘n’=participants with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
    Notes
    [13] - 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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: score on a scale
    least squares mean (standard error)
        GHS/QoL (n = 130, 125)
    1.8 ( 1.6 )
    2.5 ( 1.6 )
        Physical functioning (n = 131, 126)
    -1.2 ( 1.3 )
    -3.1 ( 1.3 )
        Role functioning (n = 131, 126)
    -2.4 ( 1.9 )
    -3.0 ( 1.8 )
        Emotional functioning (n = 131, 126)
    -2.2 ( 1.7 )
    3.0 ( 1.6 )
        Cognitive functioning (n = 131, 126)
    -0.9 ( 1.6 )
    -0.8 ( 1.5 )
        Social functioning (n = 130, 126)
    -2.5 ( 1.7 )
    -0.8 ( 1.7 )
        Fatigue (n = 131, 126)
    1.1 ( 1.9 )
    2.8 ( 1.9 )
        Nausea and vomiting (n = 131, 126)
    1.7 ( 1.3 )
    1.3 ( 1.3 )
        Pain (n = 131, 126)
    1.1 ( 1.9 )
    2.1 ( 1.9 )
        Dyspnoea (n = 131, 125)
    1.0 ( 1.6 )
    0.8 ( 1.6 )
        Insomnia (n = 131, 126)
    -1.1 ( 2.3 )
    -2.3 ( 2.2 )
        Appetite loss (n = 130, 126)
    2.4 ( 2.3 )
    1.2 ( 2.3 )
        Constipation (n = 131, 126)
    -2.3 ( 2.0 )
    3.0 ( 2.0 )
        Diarrhoea (n= 130, 126)
    0.3 ( 1.3 )
    3.9 ( 1.3 )
        Financial difficulties (n= 131, 126)
    1.7 ( 1.8 )
    -2.0 ( 1.8 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value

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    End point title
    		 Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value [14]
    End point description
    EQ-5D-5L:consists of 2 sections: EQ-5D-5L health state utility index (descriptive system) & VAS. EQ-5D descriptive system consists of 5 dimensions: mobility,self-care,usual activities,pain/discomfort & anxiety/depression.Each dimension has 5 levels:no problems,slight problems,moderate problems,severe problems,& extreme problems. Response options measured with 5-point Likert scale (for 5L version).EQ-5D-5L responses are converted into single index utility score between 0 to 1,higher score:better health state & lower score indicate worse health state.LS mean and SE are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values overall treatment (i.e., each cycle [Cycle 1 up to Cycle 30]) was reported.Safety population evaluable.Here, ‘number of subjects analyzed’=participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    124
    129
    Units: score on a scale
        least squares mean (standard error)
    -0.0 ( 0.0 )
    -0.0 ( 0.0 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score

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    End point title
    		 Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score [15]
    End point description
    EQ-5D-5L:standardized measure of health status, provides simple, generic measure of health for clinical and economic appraisal, consists of 2 sections: EQ-5D-5L health state utility index (descriptive system) & EQ-5D-5L VAS. VAS designed to rate participant's current health state on a scale from 0 to 100, 0:worst imaginable health state and 100: best imaginable health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 30]) was reported. Safety population evaluable: participants randomly assigned to study intervention, who took at least 1 dose of study intervention, completed Baseline, at least 1 post Baseline on-treatment assessment. Here, ‘number of subjects analyzed’=participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    125
    125
    Units: score on a scale
        least squares mean (standard error)
    0.9 ( 1.4 )
    0.2 ( 1.4 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores [16]
    End point description
    QLQ-BR23:disease-specific Health-related QOL.EORTC-QLQ-BR23 contains 23 items:multi-item scales & single-item measures. 4 functional scales (body image,sexual functioning,sexual enjoyment,future perspective) & 4 scales related to symptoms of disease/treatment (arm symptoms,breast symptoms,systemic therapy side effects,& upset by hair loss).All items scored 1(not at all) to 4(very much).Scores of all scales transformed from raw scores to linear scales ranging 0 to 100.Higher score(functional scales)=better outcome;higher score(symptoms scales)=higher symptom burden.LS mean and SE derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle [Cycle 1 up to Cycle 30]) was reported. Safety population evaluable. ‘n’ = participants with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
    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: Data for this endpoint was evaluated for Main cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort
    Number of subjects analysed
    147
    143
    Units: score on a scale
    least squares mean (standard error)
        Body image (n = 132, 130)
    1.8 ( 1.7 )
    2.2 ( 1.6 )
        Sexual functioning (n = 127, 127)
    -2.4 ( 1.3 )
    -2.6 ( 1.2 )
        Sexual enjoyment (n = 33, 20)
    -1.1 ( 3.0 )
    0.4 ( 4.1 )
        Future perspective (n= 132,130)
    10.6 ( 2.7 )
    12.0 ( 2.6 )
        Systemic therapy side effects (n = 133, 130)
    0.2 ( 1.0 )
    0.7 ( 1.0 )
        Breast symptoms (n = 129, 128)
    -0.4 ( 1.3 )
    -0.8 ( 1.2 )
        Arm symptoms (n = 130, 128)
    1.8 ( 1.7 )
    2.0 ( 1.7 )
        Upset by hair loss (n = 37, 47)
    -9.7 ( 3.9 )
    -10.6 ( 3.7 )
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Percentage of Participants With Objective Response

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    End point title
    		 Chinese Cohort: Percentage of Participants With Objective Response [17]
    End point description
    Objective response is defined as percentage of participants having a PR or CR according to the RECIST version 1.1 assessed by ICR. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Analysis was performed on the ITT population. Only those participants with response are reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    37
    46
    Units: percentage of participants
        number (confidence interval 95%)
    10.8 (3.0 to 25.4)
    6.5 (1.4 to 17.9)
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Overall Survival

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    End point title
    		 Chinese Cohort: Overall Survival [18]
    End point description
    OS is defined as the time interval from the date of randomization to the date of documented death (due to any cause). In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. Analysis was performed on the ITT population. Here, '99999' is used as a space filler and denotes that median, upper and lower limits of 95% CI were not estimable due to insufficient number of participants with events at study termination.
    End point type
    Secondary
    End point timeframe
    From randomization to the death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks)
    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: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    42
    48
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Percentage of Participants With Disease Control

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    End point title
    		 Chinese Cohort: Percentage of Participants With Disease Control [19]
    End point description
    Disease control:percentage of participants having a confirmed CR, PR, or SD or Non-CR/Non-PD as BOR determined by ICR as per RECIST 1.1 from date of randomization to date of end of treatment. As per RECIST 1.1, CR:disappearance of all target and non-target lesions and normalization of tumor marker level.Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR:at least a 30% decrease in sum of diameters of target lesions,taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Non-CR/Non-PD:persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above normal limits. PD:at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.Analysis was performed on ITT population. Only those participants with response are reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks)
    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: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    37
    46
    Units: percentage of participants
        number (confidence interval 95%)
    75.7 (58.8 to 88.2)
    73.9 (58.9 to 85.7)
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Percentage of Participants With Clinical Benefit

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    End point title
    		 Chinese Cohort: Percentage of Participants With Clinical Benefit [20]
    End point description
    Clinical benefit:percentage of participants having a confirmed CR,PR,SD,or Non-CR/Non-PD for at least 24 weeks determined by ICR as per RECIST 1.1 from date of randomization to date of end of treatment.As per RECIST 1.1,CR:disappearance of all target and non-target lesions and normalization of tumor marker level.Any pathological lymph nodes(whether target/non-target) must have reduction in short axis to <10 mm.PR:at least a 30% decrease in sum of diameters of target lesions,taking as reference the baseline sum diameters.SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,taking as reference the smallest sum diameters.Non-CR/Non-PD:persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above normal limits.PD:at least 20% increase in sum of diameters of target lesions,unequivocal progression of existing non-target lesions.Analysis was performed on ITT population.Only those participants with response are reported.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks)
    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: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    37
    46
    Units: percentage of participants
        number (confidence interval 95%)
    21.6 (9.8 to 38.2)
    23.9 (12.6 to 38.8)
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Duration of Response

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    End point title
    		 Chinese Cohort: Duration of Response [21]
    End point description
    DOR: time (in months) from first documented evidence of CR or PR until PD determined by ICR as per RECIST 1.1 or death from any cause, whichever occurs first. For participants with ongoing response at time of analysis,DOR was censored at the date of last valid disease assessment not showing documented progression performed before initiation of a new anticancer treatment (if any).As per RECIST 1.1,CR:disappearance of all target and non-target lesions and normalization of tumor marker level.Any pathological lymph nodes (whether target/non-target) must have reduction in short axis to <10 mm.PR:at least a 30% decrease in sum of diameters of target lesions,taking as reference baseline sum diameters.PD:at least 20% increase in sum of diameters of target lesions,unequivocal progression of existing non-target lesions. Subset of ITT population who had an objective response. Here, '99999': values were not estimable due to insufficient number of participants with events at study termination.
    End point type
    Secondary
    End point timeframe
    From the date of first response to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    4
    3
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Progression Free Survival According to Estrogen Receptor 1 Gene Mutation Status

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    End point title
    		 Chinese Cohort: Progression Free Survival According to Estrogen Receptor 1 Gene Mutation Status [22]
    End point description
    PFS:time(in months) interval from date of randomization to date of first documented tumor progression as per RECIST 1.1 assessed by ICR or death(due to any cause), whichever comes first.Progression as per RECIST 1.1:at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.Mutation status(wild type,mutant) of twelve specific mutations of ESR1 gene was determined by multiplex ddPCR.PFS is reported based on ESR1 mutation status of participants:wild type and mutants.ESR1:gene encoding estrogen receptor alpha.ESR1 mutant type breast cancer:disease where ESR1 gene had a mutation (type of error).ESR1 wild type breast cancer:disease where ESR1 gene was normal without a mutation. ITT population.‘n’= participants with available data for each specified category. ‘+/-9999’:insufficient numbers of participants with 1/2 participants censored prior to any event. '99999': insufficient number of participants with events at study termination.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    5
    3
    Units: months
    median (confidence interval 95%)
        Mutated (n = 2, 3)
    5.5 (-9999 to 9999)
    1.8 (1.7 to 99999)
        Wild type (n = 5, 3)
    99999 (1.8 to 99999)
    1.9 (1.8 to 99999)
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Plasma Concentration of Amcenestrant

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    End point title
    		 Chinese Cohort: Plasma Concentration of Amcenestrant [23]
    End point description
    Amcenestrant plasma concentrations at specified time points are reported. Analysis was performed on Pharmacokinetic-evaluable population: all participants who were assigned to study intervention, took at least 1 dose of study intervention, had at least 1 available plasma concentration post treatment with adequate documentation of date and time of dosing and date and time of sampling. Here, ‘n’ = participants with available data for each specified category. Data for this outcome measure was not planned to be collected and analyzed for PCEM group arm.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 1.5 hours(h), 4h post-dose, Cycle 1 Day 15: pre-dose; Cycle 2 Day 1: pre-dose, 1.5h, 4h, 8h post-dose; Cycles 3, 4, and 6 Day 1: pre-dose
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analyzed for PCEM arm.
    End point values
    		 Amcenestrant- Chinese Cohort
    Number of subjects analysed
    46
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 1.5h (n = 35)
    3643.3 ( 3166.2 )
        Cycle 1 Day 1: 4h (n = 46)
    6015.0 ( 2887.0 )
        Cycle 1 Day 15: Pre-dose (n = 31)
    694.3 ( 589.4 )
        Cycle 2 Day 1: Pre-dose (n = 43)
    553.2 ( 316.9 )
        Cycle 2 Day 1: 1.5h (n = 30)
    3318.1 ( 3097.9 )
        Cycle 2 Day 1: 4h (n = 31)
    4912.9 ( 2513.9 )
        Cycle 2 Day 1: 8h (n = 30)
    3309.7 ( 1318.7 )
        Cycle 3 Day 1: Pre-dose (n = 37)
    521.6 ( 439.9 )
        Cycle 4 Day 1: Pre-dose (n = 30)
    475.1 ( 301.2 )
        Cycle 6 Day 1: Pre-dose (n = 16)
    598.5 ( 379.1 )
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Domain Scores

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    End point title
    		 Chinese Cohort: Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Domain Scores [24]
    End point description
    EORTC-QLQ-C30:cancer-specific instrument with 30 questions for evaluation of new chemotherapy & assessment of participant reported outcome.These include 5 functional scales, 9 symptom scales, & GHS/QoL. All 14 items/domains were scored on scale of 1 (not at all) to 4 (very much) and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional & GHS/QoL = higher level of functioning, & higher score for symptoms scales = higher symptom burden. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle [Cycles 2, 3, 4 and 6]) was reported. Safety population. Here, ‘n’ = participants with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycles 2, 3, 4 and 6 [i.e., 183 weeks])
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    35
    39
    Units: score on a scale
    least squares mean (standard error)
        GHS/QoL (n = 35, 38)
    6.4 ( 2.6 )
    0.3 ( 2.5 )
        Physical functioning (n = 35, 39)
    4.3 ( 1.4 )
    0.9 ( 1.3 )
        Role functioning (n = 35, 39)
    -1.9 ( 2.5 )
    -0.1 ( 2.4 )
        Emotional functioning (n = 35, 39)
    -1.0 ( 2.0 )
    -1.7 ( 1.9 )
        Cognitive functioning (n = 35, 39)
    -0.4 ( 2.0 )
    -2.5 ( 1.9 )
        Social functioning (n = 35, 39)
    3.0 ( 2.3 )
    -1.9 ( 2.2 )
        Fatigue (n = 35, 39)
    -1.4 ( 2.1 )
    0.8 ( 2.0 )
        Nausea and vomiting (n = 35, 39)
    -0.9 ( 1.9 )
    0.9 ( 1.8 )
        Pain (n = 35, 39)
    -2.1 ( 2.1 )
    -2.3 ( 2.0 )
        Dyspnoea (n = 35, 39)
    -0.3 ( 2.5 )
    2.3 ( 2.4 )
        Insomnia (n = 35, 39)
    -0.9 ( 2.5 )
    -1.4 ( 2.4 )
        Appetite loss (n = 35, 39)
    -1.9 ( 2.7 )
    2.3 ( 2.6 )
        Constipation (n = 35, 39)
    2.3 ( 2.1 )
    2.8 ( 2.0 )
        Diarrhoea (n = 35, 39)
    -0.7 ( 1.1 )
    -0.2 ( 1.1 )
        Financial difficulties (n = 35, 38)
    -7.3 ( 3.3 )
    -6.4 ( 3.2 )
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Visual Analog Scale Score

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    End point title
    		 Chinese Cohort: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Visual Analog Scale Score [25]
    End point description
    EQ-5D-5L is a standardized measure of health status, provides a simple, generic measure of health for clinical and economic appraisal, and consists of 2 sections: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L VAS. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle [Cycles 2, 3, 4 and 6]) was reported in this outcome measure. Analysis was performed on Safety population evaluable. Here, “number of subjects analyzed” signifies participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycles 2, 3, 4 and 6 [i.e.,183 weeks])
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    35
    39
    Units: score on a scale
        least squares mean (standard error)
    3.6 ( 1.3 )
    1.2 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Health Utility Index Value

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    End point title
    		 Chinese Cohort: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Health Utility Index Value [26]
    End point description
    EQ-5D-5L:consists of 2 sections:EQ-5D-5L health state utility index(descriptive system) & VAS.EQ-5D descriptive system consists of 5 dimensions:mobility,self-care,usual activities, pain/discomfort & anxiety/depression.Each dimension has 5 levels:no problems,slight problems,moderate problems,severe problems,& extreme problems.Response options are measured with 5-point Likert scale(for 5L version).EQ-5D-5L responses are converted into single index utility score between 0 to 1,higher score:better health state & lower score:worse health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable,treatment, time,treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values overall treatment (i.e., each cycle [Cycles 2, 3, 4 and 6]) was reported.Safety population evaluable. ‘Number of subjects analyzed’=participants with available data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycles 2, 3, 4 and 6 [i.e.,183 weeks])
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    35
    40
    Units: score on a scale
        least squares mean (standard error)
    -0.0 ( 0.0 )
    0.0 ( 0.0 )
    No statistical analyses for this end point

    Secondary: Chinese Cohort: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module Domain Scores

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    End point title
    		 Chinese Cohort: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module Domain Scores [27]
    End point description
    QLQ-BR23:disease-specific Health-related QOL.EORTC-QLQ-BR23 had 23 items:multi-item scales & single-item measures.4 functional scales(body image,sexual functioning,sexual enjoyment,future perspective) & 4 scales related to symptoms of disease or treatment(arm symptoms,breast symptoms,systemic therapy side effects,& upset by hair loss).All items scored 1(not at all) to 4(very much).Scores of all scales transformed from raw scores to linear scales,range:0 to 100.Higher score(functional):better outcome;higher score(symptoms):higher symptom burden.LS mean & SE derived from MMRM model with change from baseline values as response variable,treatment,time,treatment-by-time interaction,Baseline value & stratifications factors as fixed effect.Average of LS mean change from baseline values of overall treatment(each cycle[Cycles 2,3,4 & 6]).‘Number of subjects analyzed': participants with available data for this outcome measure.Only items with atleast 10 participants by treatment group included.
    End point type
    Secondary
    End point timeframe
    Baseline, overall treatment duration (Cycles 2, 3, 4 and 6 [i.e.,183 weeks])
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was evaluated for Chinese cohort only.
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    36
    40
    Units: score on a scale
    least squares mean (standard error)
        Body image
    -0.8 ( 2.4 )
    0.2 ( 2.3 )
        Sexual functioning
    -1.6 ( 1.3 )
    -3.6 ( 1.3 )
        Future perspective
    8.3 ( 3.2 )
    5.1 ( 3.0 )
        Systemic therapy side effects
    -0.5 ( 1.1 )
    0.5 ( 1.0 )
        Breast symptoms
    0.8 ( 1.7 )
    0.5 ( 1.6 )
        Arm symptoms
    -0.4 ( 1.4 )
    -0.8 ( 1.4 )
    No statistical analyses for this end point

    Secondary: Main Cohort and Chinese Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Main Cohort and Chinese Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was a medically important event. TEAEs were defined as AEs that developed, worsened (according to the Investigator’s opinion), or became serious during the on-treatment period. Analysis was performed on Safety population evaluable.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Cycle 1 Day 1) up to 152 weeks for main cohort and 183 weeks for Chinese cohort
    End point values
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Main Cohort Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Chinese Cohort
    Number of subjects analysed
    147
    143
    42
    48
    Units: participants
        Any TEAE
    113
    118
    22
    33
        Any TESAE
    16
    25
    2
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs: From first dose of study treatment (Cycle 1 Day 1) up to 152 weeks (main cohort) and 183 weeks (Chinese cohort). Deaths: First dose of study drug (Day 1) to the end of follow-up for death for each participant, up to approximately 761 days
    Adverse event reporting additional description
    Analysis was performed on Safety population evaluable.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort
    Reporting group description
    		 Participants received potential control treatment of the choice of the physician depending on each participant’s medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-mL IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg) PO, QD; or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum exposure: 116 weeks).

    Reporting group title
    Amcenestrant- Chinese Cohort
    Reporting group description
    		 Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant's request to stop treatment or Investigator decision, whichever occurred first (maximum treatment exposure: 183 weeks).

    Reporting group title
    Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort
    Reporting group description
    		 Participants received potential control treatment of the choice of the physician depending on each participant's medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-mL IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg) PO, QD; or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum treatment exposure: 183 weeks).

    Reporting group title
    Amcenestrant- Main Cohort
    Reporting group description
    		 Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant’s request to stop treatment or Investigator decision, whichever occurred first (maximum exposure: 116 weeks).

    Serious adverse events
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Chinese Cohort Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Main Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 147 (10.88%)
    5 / 48 (10.42%)
    2 / 42 (4.76%)
    25 / 143 (17.48%)
         number of deaths (all causes)
    52
    6
    2
    46
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    5 / 143 (3.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 5
    Death
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Contrast Media Allergy
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast Pain
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 147 (2.72%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Pleural Effusion
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    1 / 42 (2.38%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Respiratory Distress
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    1 / 42 (2.38%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    3 / 147 (2.04%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Peritonitis Bacterial
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Abscess
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Physician Choice Endocrine Monotherapy (PCEM)- Main Cohort Amcenestrant- Chinese Cohort Physician Choice Endocrine Monotherapy (PCEM)- Chinese Cohort Amcenestrant- Main Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 147 (53.74%)
    25 / 48 (52.08%)
    14 / 42 (33.33%)
    86 / 143 (60.14%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    13 / 147 (8.84%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    13 / 143 (9.09%)
         occurrences all number
    13
    1
    0
    13
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 147 (10.20%)
    3 / 48 (6.25%)
    1 / 42 (2.38%)
    18 / 143 (12.59%)
         occurrences all number
    16
    3
    1
    19
    General disorders and administration site conditions
    Injection Site Pain
         subjects affected / exposed
    10 / 147 (6.80%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences all number
    21
    0
    0
    0
    Fatigue
         subjects affected / exposed
    17 / 147 (11.56%)
    4 / 48 (8.33%)
    1 / 42 (2.38%)
    16 / 143 (11.19%)
         occurrences all number
    18
    4
    1
    18
    Asthenia
         subjects affected / exposed
    8 / 147 (5.44%)
    1 / 48 (2.08%)
    1 / 42 (2.38%)
    11 / 143 (7.69%)
         occurrences all number
    8
    1
    1
    16
    Pyrexia
         subjects affected / exposed
    5 / 147 (3.40%)
    3 / 48 (6.25%)
    1 / 42 (2.38%)
    5 / 143 (3.50%)
         occurrences all number
    5
    3
    2
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 147 (7.48%)
    5 / 48 (10.42%)
    4 / 42 (9.52%)
    7 / 143 (4.90%)
         occurrences all number
    11
    7
    4
    9
    Nausea
         subjects affected / exposed
    13 / 147 (8.84%)
    3 / 48 (6.25%)
    1 / 42 (2.38%)
    28 / 143 (19.58%)
         occurrences all number
    14
    3
    1
    36
    Diarrhoea
         subjects affected / exposed
    9 / 147 (6.12%)
    1 / 48 (2.08%)
    1 / 42 (2.38%)
    14 / 143 (9.79%)
         occurrences all number
    10
    1
    2
    20
    Vomiting
         subjects affected / exposed
    5 / 147 (3.40%)
    3 / 48 (6.25%)
    1 / 42 (2.38%)
    27 / 143 (18.88%)
         occurrences all number
    5
    3
    1
    43
    Abdominal Pain
         subjects affected / exposed
    5 / 147 (3.40%)
    0 / 48 (0.00%)
    0 / 42 (0.00%)
    8 / 143 (5.59%)
         occurrences all number
    5
    0
    0
    9
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 48 (2.08%)
    0 / 42 (0.00%)
    8 / 143 (5.59%)
         occurrences all number
    1
    2
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 147 (5.44%)
    6 / 48 (12.50%)
    6 / 42 (14.29%)
    7 / 143 (4.90%)
         occurrences all number
    8
    6
    7
    7
    Dyspnoea
         subjects affected / exposed
    11 / 147 (7.48%)
    2 / 48 (4.17%)
    1 / 42 (2.38%)
    7 / 143 (4.90%)
         occurrences all number
    11
    2
    1
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 147 (2.72%)
    1 / 48 (2.08%)
    1 / 42 (2.38%)
    9 / 143 (6.29%)
         occurrences all number
    4
    1
    1
    10
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    10 / 147 (6.80%)
    2 / 48 (4.17%)
    0 / 42 (0.00%)
    8 / 143 (5.59%)
         occurrences all number
    10
    2
    0
    9
    Back Pain
         subjects affected / exposed
    17 / 147 (11.56%)
    1 / 48 (2.08%)
    2 / 42 (4.76%)
    18 / 143 (12.59%)
         occurrences all number
    19
    1
    3
    20
    Arthralgia
         subjects affected / exposed
    14 / 147 (9.52%)
    2 / 48 (4.17%)
    0 / 42 (0.00%)
    18 / 143 (12.59%)
         occurrences all number
    14
    2
    0
    22
    Infections and infestations
    Covid-19
         subjects affected / exposed
    3 / 147 (2.04%)
    3 / 48 (6.25%)
    2 / 42 (4.76%)
    2 / 143 (1.40%)
         occurrences all number
    3
    3
    2
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    7 / 147 (4.76%)
    2 / 48 (4.17%)
    1 / 42 (2.38%)
    10 / 143 (6.99%)
         occurrences all number
    7
    2
    1
    11
    Hypocalcaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    3 / 48 (6.25%)
    1 / 42 (2.38%)
    0 / 143 (0.00%)
         occurrences all number
    0
    6
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    3 / 48 (6.25%)
    0 / 42 (0.00%)
    0 / 143 (0.00%)
         occurrences all number
    0
    6
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2019
    Following Changes were made: Text in schema was updated as OS follow-up every 2 months until 18 months after PFS cut-off date; Updated tumor assessment schedule, bone scan schedule, tumor specimen/biopsy schedule; Cut-off date for the presentation of TED14856 results updated from 22 October 2018 to 29 May 2019; Amcenestrant benefit information updated to align with the updated Investigator’s Brochure as number of participants with stable disease updated from 7 to 8; number of participants with long-term stable disease updated from 3 to 7; clinical benefit observed in 8 participants; Amcenestrant safety information updated as treatment-emergent adverse event results from TED14856 study Part A included; Remaining information removed and referred to the Investigator’s Brochure; exploratory endpoint updated as to align with the updated schedule for ESR1 analysis and with the updated tumor specimen/biopsy schedule; Updated pharmacokinetic information related to Amcenestrant obtained from healthy volunteers and participants was included, updates to exclude participants with high thromboembolic risk; Clarified screen failures; Clarified dispensing and shipping procedures for IMP in case of direct to participant shipment of IMPs; Clarified recall procedures; Clarified dose modifications and management of amcenestrant toxicities; Clarified bone scan procedures when no lesions detected at screening; Clarified AE collection procedures; text updated to comply with the Sponsor standard procedures in Biomarker section; Clarified the statistical hypotheses; clarified the PFS censoring procedures; Clarified the DOR censoring procedures; clarified consenting procedures; Consistent updates made in appendices with the protocol amendment.
    13 Feb 2020
    Following Changes were made:Protocol title,short title updated;The NCT number included NCT04059484;Updated synopsis & schema for clarity,Screening assessment for follicle-stimulating hormone & estradiol assessment for premenopausal women was added; New assessments were added to the schedule of activities:Estradiol,Genetic sampling for drug metabolising enzymes & transporters (amcenestrant treatment arm only);Updated to include the most up to date information on potential amcenestrant risks anticipated in humans; Overall survival was relocated as the first secondary objective; Clarified that men were included in study; Updates made to align with possible dosing regimens for tamoxifen, as per label; COD projections updated following newly added futility interim analysis for PFS & inclusion of OS as key secondary endpoint; COD definitions updated for clarity;Recruitment period for Chinese population extended after sample size was revised for this population;Contraceptive guidance for male participants was included; participants with bone-only metastasis were allowed in this study; clarified to include all potential UGT inhibitors;Time window for amcenestrant dosing added; Updates that participants that were benefiting from the medication to continue treatment after a delay longer than 2 weeks;Clarified concomitant administration of strong and moderate CYP3A4 inducers and moderate CYP2C8 inducers was not to be permitted in participants receiving amcenestrant, since they may decrease amcenestrant exposure;Estradiol assessments included to explore the possible influence of circulating levels of estradiol on the efficacy of amcenestrant; A new section included for investigation of allelic variants of drug metabolising enzymes and/or drug transporters; clarified statistical hypotheses for the key secondary endpoint (OS);Sample size calculation updated in accordance with newly added futility interim analysis for PFS. Improvement in median PFS was corrected from 35 to 53%.
    30 Jun 2020
    Following changes were made: Introduced of study name AMEERA 3; Updates to allow some flexibility in the assessment of the vital signs following the first intake of the IMP; updates to specify Estradiol sampling at predose; Contingency measures for a regional or national emergency information added; potential risk related to amcenestrant added as risk of severe rash; tertiary/exploratory objective and endpoint have were updated to indicate that the biopsies were optional; updates to clarify the scope of Data Monitoring Committee (DMC) responsibility - as the interim analyses on Overall Survival will happen at the time of final Progression Free Survival, treatment would be unblinded and thus there was no need for DMC at that time; Updates to specify that the previous treatment with a CDK 4/6 inhibitor and the limitation to the number of participants naïve to CDK4/6 inhibitors does not apply to the participants of the extension study; Clarified and harmonised the definition of Human epidermal growth factor receptor (HER) non over-expressing tumors; Updates to mark biopsy procedures was categorised as optional; definition of secondary endocrine resistance updated; definition of a “sexually active male” clarified; duration of avoiding the natural or artificial sunlight exposure updated; the assessment of the estrogen receptor degradation with the biopsies, updated as optional; harmonised the wording of the samples’ storage with the informed consent form.
    17 Dec 2020
    Following changes were made: The definitions of Disease Control Rate (DCR) and Clinical Benefit Rate (BCR) have been updated to add the “Non-Complete Response/Non-Progressive Disease” in the endpoint’s descriptions; Texts updated to take in account that Estradiol levels can be high due to Fulvestrant intake; Added clarification on bone scans schedule; Risk of male infertility was added; Updated exclusion criteria with new data available on drug interactions (BCRP substrates, CYP3A and CYP2C8 inducers); Revised the futility analysis; to add risk minimisation strategies for pregnancy, osteoporosis induced by endocrine therapies, hepatic toxicity, and photosensitivity; Adverse events of special interests (AESI) section updated to provide guidance in case of an ALT increase; deleted a section which could be misunderstood in the AEs/SAEs reporting process; Clarification added on PROs schedule, to take in account that end of treatment (EOT) visit can be performed before 30 days following last IMP (if further therapy is started); Text added to allow remote-monitoring when allowed by local regulations, if on-site monitoring is not possible; Clarified that renal function calculation needed on top of the creatinine level for all participants; Updates in collection of pregnancy information; List of CYP sensitive substrates were updated; Added a copy of the following PROs English-language questionnaires: EORTC QLQ-C30, EORTC BR-23 (for female and male participants) and EQ-5D-5L.
    23 Sep 2021
    Following changes were made: Updates to clarify that after COD for final PFS analysis, data collected would be limited to exposure data, reason of EOT, and safety events and its related information when adverse event is serious or related to IMP; For planned cutoff date (previously database lock date) for the Chinese participants, sentence removed i.e., approximately 18 months after the PFS analysis of the global study; Exclusion criterion was adjusted to remove sensitive substrates of P-gp and BCRP and add sensitive substrates of OATP1B1/B3. And a note was added under this exclusion criteria to refer to FDA website; Sensitive substrates of P-gp and BCRP related information was removed, sensitive substrates of OATP1B1/B3 related information added to concomitant therapy section; Text removed to update caution to be taken with the proton pump inhibitors; Clarified the responsibilities for the monitoring, as a commitment to Belgium Health Authority requirement; Clarified that only amcenestrant is in scope of this ‘recommended dose modification’ table; Updated the required PK samples of the “full-PK” population in China, when sampling is difficult for participants; Clarified that specificities regarding exploratory endpoints in China per local regulations apply also for participants from China enrolled in the global part of the study; Clarified the sample size determination section, and to clarify the current definition of the COD rule for the Chinese population; Clarified that participants who agree to have samples taken for the full PK assessments were required to sign a separate section of the ICF rather than a separate ICF; Correction of typographical errors and minor inconsistencies across different sections, and clarifications were aligned with latest protocol template.
    10 Dec 2021
    Following updates were made: The definition of the COD for the final PFS and OS analysis was changed; The definition of the censoring and event scheme for the PFS analysis was changed; text added to clarify that SAEs are in scope of data to be collected post-COD, even if not related to IMP.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early because it did not meet its primary objective of improved PFS with amcenestrant versus endocrine treatment of physician's choice.
    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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