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    Clinical Trial Results:
    The [PEARL] Study : Pet imaging as a biomarker of Everolimus Added value in hormone Refractory postmenopausaL women

    Summary
    EudraCT number
    		 2012-004860-22
    Trial protocol
    		 BE  
    Global end of trial date
    06 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions
    Summary report(s)
    		 PEARL_final_report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IJB-BCTL:20120306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut Jules Bordet
    Sponsor organisation address
    Rue Meylemeersch,90, Brussels, Belgium, 1070
    Public contact
    Andrea Gombos, institut Jules Bordet, 32 2541 7232, andrea.gombos@bordet.be
    Scientific contact
    Andrea Gombos, institut Jules Bordet, 0472568124 2541 7232, andrea.gombos@bordet.be
    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
    09 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if early metabolic response (MR) using FDG-PET/CT is associated with progression free survival (PFS) in ER+, HER2 negative ABC or MBC patients treated with exemestane plus everolimus.
    Protection of trial subjects
    insurance
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    51
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Belgium pilot phase - inclusion of patients from February 2014 till June 2016 main phase - inclusion of patients from June 2017 till May 2018

    Pre-assignment
    Screening details
    		 Screening assessments to confirm eligibility must be performed prior to the first dose of studydrug. Physical examination including performance status, height and weight must be performed within 21 days prior to the first dose of study treatment.

    Period 1
    Period 1 title
    Pilot and main phases
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Main phase
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5.0 mg and 10 mg strength for oral administration

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg strength for oral administration

    Arm title
    		 Pilot phase
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5.0 mg and 10 mg strength for oral administration

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg strength for oral administration

    Number of subjects in period 1
    		Main phase Pilot phase
    Started
    20
    44
    Completed
    20
    27
    Not completed
    0
    17
         increase of liver function tests
    -
    1
         not evaluable for PET
    -
    6
         HER2+ on baseline biopsy
    -
    2
         no PET measurable lesion
    -
    8
    Period 2
    Period 2 title
    Evaluable subjects (ITT)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Evaluable subjects (ITT)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5.0 mg and 10 mg strength for oral administration

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg strength for oral administration

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics are provided for evaluable subjects.
    Number of subjects in period 2 [2]
    		Evaluable subjects (ITT)
    Started
    47
    Completed
    47
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Analyzes have been performed on evaluable subjects.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Evaluable subjects (ITT)
    Reporting group description
    		 -

    Reporting group values
    		 Evaluable subjects (ITT) Total
    Number of subjects
    		 47 47
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ( 13.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 47
        Male
    		 0 0
    ECOG PS
    Units: Subjects
        Zero
    		 23 23
        One
    		 23 23
        Two
    		 1 1
    Histology
    Units: Subjects
        Invasive ductal
    		 38 38
        Invasive lobular
    		 8 8
        Unknown
    		 1 1
    Grade
    Units: Subjects
        G1
    		 8 8
        G2
    		 17 17
        G3
    		 11 11
        Unknown
    		 11 11
    Current disease status
    Units: Subjects
        Metastatic
    		 45 45
        Locally advanced
    		 2 2
    Current disease status
    Units: Subjects
        Metastatic Lung or liver
    		 35 35
        Metastatic Bone only
    		 6 6
        Metastatic Other
    		 4 4
        Locally advanced
    		 2 2
    N Metastatic sites
    Units: Subjects
        Zero
    		 2 2
        1‐2
    		 24 24
        ≥3
    		 21 21
    KI‐67 (primary)
    Units: Subjects
        <10%
    		 5 5
        10%‐15%
    		 6 6
        16%‐25%
    		 9 9
        >25%
    		 17 17
        Unknown
    		 10 10
    Prior CDK 4/6
    Units: Subjects
        No
    		 35 35
        Yes
    		 12 12
    Number of lines CT in advanced setting
    Units: Subjects
        Zero
    		 20 20
        One
    		 14 14
        ≥2
    		 13 13
    Number of lines ET in advanced setting
    Units: Subjects
        Zero
    		 2 2
        One
    		 13 13
        ≥2
    		 32 32
    NSAI sensitive
    Units: Subjects
        No
    		 13 13
        Yes
    		 34 34
    Subjects who continued exemestane after having stopped everolimus
    Units: Subjects
        Yes
    		 13 13
        No
    		 34 34
    Subjects who continued exemestane more than a month after having stopped everolimus
    Units: Subjects
        Yes
    		 5 5
        No
    		 42 42
    Subjects with treatment interruption of exemestane (protocol violation)
    Units: Subjects
        Yes
    		 1 1
        No
    		 46 46
    Subjects with treatment interruption everolimus
    Units: Subjects
        Yes
    		 23 23
        No
    		 24 24
    Subjects with dose reduction everolimus (from 10 till 5)
    Units: Subjects
        Yes
    		 21 21
        No
    		 26 26
    Days between baseline PET and start treatment
    Units: Subjects
        1 - 7 days
    		 36 36
        8-14 days
    		 9 9
        ≥15 days
    		 2 2
    Days between start treatment and PET D14
    Units: Subjects
        12
    		 2 2
        13
    		 5 5
        14
    		 32 32
        15
    		 6 6
        16
    		 1 1
        17
    		 1 1
    Duration everolimus treatment
    (=from start everolimus till last day everolimus)
    Units: months
        arithmetic mean (standard deviation)
    		 5.5 ( 5.2 ) -
    Duration everolimus treatment
    (=from start everolimus till last day everolimus)
    Units: months
        median (full range (min-max))
    		 4.1 (1 to 29) -
    Duration exemestane treatment
    (= from start exemestane till last day exemestane )
    Units: months
        arithmetic mean (standard deviation)
    		 6.2 ( 5.5 ) -
    Duration exemestane treatment (in months)
    (= from start exemestane till last day exemestane )
    Units: months
        median (full range (min-max))
    		 5 (1.6 to 29) -

    End points

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    End points reporting groups
    Reporting group title
    Main phase
    Reporting group description
    		 -

    Reporting group title
    Pilot phase
    Reporting group description
    		 -
    Reporting group title
    Evaluable subjects (ITT)
    Reporting group description
    		 -

    Subject analysis set title
    F-FDG-PET/CT response on D14 Consist 25%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    subjects with a SUVmax reduction of more than 25% in all lesions classified as responders

    Subject analysis set title
    F-FDG-PET/CT non-response on D14 Consist 25%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    subjects with a SUVmax reduction of less than or equal to 25% in all lesions classified as responders

    Subject analysis set title
    F-FDG-PET/CT response on D14 Consist 15%("post-hoc")
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with a > 15 % homogenous decrease in maximum standardized uptake value (SUVmax) in all target lesions are considered as “responders”. This is a “post-hoc” analysis, initially not scheduled by the study protocol.

    Subject analysis set title
    F-FDG-PET/CT non-response on D14 Consist 15%("post-hoc")
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with a > 15 % homogenous decrease in maximum standardized uptake value (SUVmax) in all target lesions are considered as “responders”. This is a “post-hoc” analysis, initially not scheduled by the study protocol.

    Primary: Time to progression

    		 Close Top of page
    End point title
    		 Time to progression
    End point description
    End point type
    Primary
    End point timeframe
    Time to progression since date of early PET, in order to adjust for guarantee-time bias
    End point values
    		 F-FDG-PET/CT response on D14 Consist 25% F-FDG-PET/CT non-response on D14 Consist 25% F-FDG-PET/CT response on D14 Consist 15%("post-hoc") F-FDG-PET/CT non-response on D14 Consist 15%("post-hoc")
    Number of subjects analysed
    15
    30
    23
    22
    Units: months
        median (inter-quartile range (Q1-Q3))
    6 (4.6 to 13.9)
    3.1 (2.3 to 5.5)
    6.4 (2.9 to 13.9)
    2.2 (1.9 to 4.9)
    Attachments
    		 Kaplan–Meier plots
    Impact of variables on PFS (univariate analysis)
    Statistical analysis title
    		 PFS according to PET scan Consist 25% on D14
    Statistical analysis description
    subjects with > 25% homogenous decrease in maximum standardized uptake value (SUVmax) in all target lesions are considered as "responders"
    Comparison groups
    F-FDG-PET/CT response on D14 Consist 25% v F-FDG-PET/CT non-response on D14 Consist 25%
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.44
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.5
    Statistical analysis title
    		 PFS according to PET scan Consist 15% on D14
    Comparison groups
    F-FDG-PET/CT response on D14 Consist 15%("post-hoc") v F-FDG-PET/CT non-response on D14 Consist 15%("post-hoc")
    Number of subjects included in analysis
    45
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.0032
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.72

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the first administration of study treatments until 28 days after the last dose of study treatments.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Safety analysis
    Reporting group description
    		 Progression of underlying malignancy is not reported as an AE if it was clearly consistent with the suspected progression of the underlying cancer. Hospitalization due solely to the progression of underlying malignancy should NOT be reported as an SAE/AE. Clinical symptoms of progression may be reported as AEs or SAEs if the symptom cannot be determined as exclusively due to the progression of the underlying malignancy, or does not fit the expected pattern of progression for the disease under study. If there is any uncertainty about an AE being due to the disease under study, it should be reported as an AE or SAE. Clinical symptoms of underlying malignancy, even if they meet a seriousness criteria, should not be reported as SAE unless the investigator considers them as more severe than expected.

    Serious adverse events
    		 Safety analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 55 (16.36%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Lung disorder
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 55 (90.91%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Hot flush
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Lymphoedema
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 55 (20.00%)
         occurrences all number
    11
    Chest pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Face oedema
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    27 / 55 (49.09%)
         occurrences all number
    28
    General physical health deterioration
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Hyperthermia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Inflammation
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Mucosal inflammation
         subjects affected / exposed
    28 / 55 (50.91%)
         occurrences all number
    36
    Oedema peripheral
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    7
    Pain
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    5
    Drug hypersensitivity
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Vulvovaginal inflammation
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Bronchospasm
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    12 / 55 (21.82%)
         occurrences all number
    13
    Dyspnoea
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    8
    Dysphonia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Dyspnoea exertional
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    21
    Epistaxis
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    6
    Interstitial lung disease
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Lung disorder
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Nasal dryness
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Nasal ulcer
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Pleural effusion
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pneumonitis
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Productive cough
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    5
    Sleep disorder
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Transaminases increased
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    6
    Weight decreased
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    6
    Weight increased
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Dysgeusia
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    10 / 55 (18.18%)
         occurrences all number
    10
    Paraesthesia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Taste disorder
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 55 (23.64%)
         occurrences all number
    14
    Hyperleukocytosis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    6
    Anal fissure
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Anorectal discomfort
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    14 / 55 (25.45%)
         occurrences all number
    15
    Dry mouth
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Dysphagia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Haemorrhoids
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    8
    Oesophagitis
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Proctalgia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Rectal haemorrhage
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Stomatitis
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    9
    Toothache
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    4
    Chest pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Alopecia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Dry skin
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    8
    Eczema
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Erythema
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Nail toxicity
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Onychalgia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Onychoclasis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Photosensitivity reaction
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    8
    Rash
         subjects affected / exposed
    17 / 55 (30.91%)
         occurrences all number
    21
    Rash maculo-papular
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Skin fissures
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Renal pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    7
    Back pain
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    5
    Bone pain
         subjects affected / exposed
    9 / 55 (16.36%)
         occurrences all number
    10
    Myalgia
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Pain in jaw
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Infections and infestations
    Bartholin's abscess
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Cystitis
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    3
    Erysipelas
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Folliculitis
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Genital herpes simplex
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Gingivitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    2
    Localised infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Mastitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Tracheitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    5
    Wound infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Skin injury
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 55 (34.55%)
         occurrences all number
    20
    Diabetes mellitus
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Dyslipidaemia
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Hypercholesterolaemia
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Hyperglycaemia
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    7
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Hypomagnesaemia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Vitamin B complex deficiency
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2014
    Protocol v2.0 : -Clarification of haematology baseline assessments -Clarification of PET timelines -Change of efficacy assessment time point form every 8 weeks to 12 weeks to be in accordance with the reimbursement conditions for Afinitor in combination with exemestane.
    15 May 2017
    Protocol v3.0 - Add Pilot phase results (Second FDG PET/CT timepoint selected for the main phase) - Main phase sample size’s recalculation - Modification of schedule of assessment - Modification of samples collection and translational researches - Clarification inclusion/exclusion criteria
    20 Jun 2017
    Protocol v4.0 : Modification of inclusion criteria
    07 Dec 2020
    Protocol v5.0 - Modification of the end of study definition - Modification of the secondary objective - Addition of a sample - Clarification regarding TR analyses

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Jun 2016
    Last subject included in the pilot phase of the study
    22 May 2017

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    There were no limitations and caveats applicable to this summary of the results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34548493
    http://www.ncbi.nlm.nih.gov/pubmed/35296682
    For support, Contact us.
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