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    Clinical Trial Results:
    A Phase IV multicenter, open label study of postmenopausal women with estrogen receptor-positive locally advanced or metastatic breast cancer treated with everolimus (RAD001) in combination with exemestane, with exploratory epigenetic marker analysis (4EVERUK)

    Summary
    EudraCT number
    		 2012-003689-41
    Trial protocol
    		 GB  
    Global end of trial date
    15 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2017
    First version publication date
    30 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001YGB11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01743560
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 6132411111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 6132411111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the Overall Response Rate (ORR) at 48 weeks to everolimus (10 mg daily p.o.) and exemestane (25 mg daily p.o.) treatment in postmenopausal women with ER+ BC who have previously experienced recurrence or progression on NSAI therapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2013
    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
    United Kingdom: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    33
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Sixty-seven patients were screened and 52 patients were enrolled. Forty-nine patients had ≥ 1 dose study drug and were considered as Started

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

    Arms
    Arm title
    		 Everolimus and Exemestane
    Arm description
    		 Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg tablets supplied and dosage was 10 mg (2 × 5 mg) p.o. per day

    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 tablets purchased locally and dosage was 1 tablet 25 mg p.o. per day

    Number of subjects in period 1
    		Everolimus and Exemestane
    Started
    49
    Completed
    9
    Not completed
    40
         Consent withdrawn by subject
    2
         Disease progression
    26
         Adverse event, non-fatal
    8
         Death
    3
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus and Exemestane
    Reporting group description
    		 Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.

    Reporting group values
    		 Everolimus and Exemestane Total
    Number of subjects
    		 49 49
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 33
        From 65-84 years
    		 16 16
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ( 8.71 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 49 49
        Male
    		 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 48 48
        Other
    		 1 1
    Study Specific Characteristic | Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 71.1 ( 15.44 ) -

    End points

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    End points reporting groups
    Reporting group title
    Everolimus and Exemestane
    Reporting group description
    		 Postmenopausal women diagnosed with oestrogen receptor positive locally advanced or metastatic breast cancer will receive everolimus at a dose of 10mg daily p.o. and exemestane 25mg daily p.o.

    Subject analysis set title
    Week 12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at week 12

    Subject analysis set title
    Week 24
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at Week 24

    Subject analysis set title
    Week 36
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at week 36

    Subject analysis set title
    Week 48
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at week 48

    Subject analysis set title
    Day 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Baseline

    Subject analysis set title
    Week 12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 12 on treatment

    Subject analysis set title
    Week 24
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 24 on treatment

    Subject analysis set title
    Week 36
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 36 on treatament

    Subject analysis set title
    Week 48
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Week 48 on treatment

    Subject analysis set title
    Week 12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at week 12

    Subject analysis set title
    Week 24
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at Week 24

    Subject analysis set title
    Week 36
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at week 36

    Subject analysis set title
    Week 48
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Change from baseline at week 48

    Primary: Best overall response of everolimus and exemestane treatment in postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer

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    End point title
    		 Best overall response of everolimus and exemestane treatment in postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer [1]
    End point description
    The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48.
    End point type
    Primary
    End point timeframe
    At 48 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical hypothesis testing was done for primary endpoint
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: participants
        Patients with measurable disease at baseline
    39
        Patients with non-measurable disease at baseline
    10
        Best at WK 48 - Complete Response (CR)
    0
        Best at WK 48 - Partial Response (PR)
    7
        Best at WK 48 - Stable Disease (SD)
    18
        Best at WK 48 - Progressive Disease (PD)
    15
        Unknown
    1
        Missing
    8
    No statistical analyses for this end point

    Primary: Overall response rate of everolimus and exemestane treatment in postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer

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    End point title
    		 Overall response rate of everolimus and exemestane treatment in postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer [2]
    End point description
    The Overall Response Rate (ORR) was defined as the proportion of patients with a best OR of confirmed CR or PR by week 48. Treatment success is defined as: The best Overall Response (OR) for each patient is determined from the sequence of investigator overall lesion responses according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1.). To be assigned a best OR of Complete Responese (CR) at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best OR of Partial Response (PR) at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.
    End point type
    Primary
    End point timeframe
    At 48 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical hypothesis testing was done for primary endpoint
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: Percentage of participants
        number (confidence interval 95%)
    14.3 (6 to 27)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) Events as per Investigators - FAS

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    End point title
    		 Progression-free Survival (PFS) Events as per Investigators - FAS
    End point description
    Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.
    End point type
    Secondary
    End point timeframe
    Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: Number of events
        Deaths
    8
        Progression of disease
    25
        Number of censored observations
    16
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) by Median Time in weeks as per Investigators - FAS

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    End point title
    		 Progression-free Survival (PFS) by Median Time in weeks as per Investigators - FAS
    End point description
    Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review.
    End point type
    Secondary
    End point timeframe
    Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: weeks
        median (confidence interval 95%)
    23.6 (12.71 to 34.29)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) - % Event-free probability estimate - FAS

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    End point title
    		 Progression-free Survival (PFS) - % Event-free probability estimate - FAS
    End point description
    Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor assessment and response was evaluated according to RECIST v1.1Response was assessed by local radiology review. The PFS was analyzed using the Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    Start of treatment to the date of event defined as first documented progression due to any cause up to approximately 48 weeks
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: Percentage of participants
    number (confidence interval 95%)
        Event free at 12 weeks
    67.9 (51.82 to 79.56)
        Event free at 24 weeks
    49.1 (32.98 to 63.44)
        Event free at 36 weeks
    28.9 (15.42 to 43.87)
        Event free at 48 weeks
    18.4 (7.38 to 33.19)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) Events as per Investigators - FAS

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    End point title
    		 Overall Survival (OS) Events as per Investigators - FAS
    End point description
    Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. Time to median OS was not estimable.
    End point type
    Secondary
    End point timeframe
    Start of treatment to the date of death up to approximately 48 weeks
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: Number of events
        Deaths
    8
        Number of censored observations
    41
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - % Event-free probability estimate - FAS

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    End point title
    		 Overall Survival (OS) - % Event-free probability estimate - FAS
    End point description
    Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    Start of treatment to the date of death up to approximately 48 weeks
    End point values
    		 Everolimus and Exemestane
    Number of subjects analysed
    49
    Units: Percentage of participants
    number (confidence interval 95%)
        Event free at 12 weeks
    93.3 (80.57 to 97.78)
        Event free at 24 weeks
    83.9 (66.92 to 92.6)
        Event free at 36 weeks
    74.2 (53.02 to 86.88)
        Event free at 48 weeks
    74.2 (53.02 to 86.88)
    No statistical analyses for this end point

    Secondary: Quality of life (EORTC Quality of Life Questionnaire of cancer patients QLQ-C30)

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    End point title
    		 Quality of life (EORTC Quality of Life Questionnaire of cancer patients QLQ-C30)
    End point description
    The QLQ-C30 is composed of multi-item scales and single-item measures including 5 functional scales, 3 symptom scales, a global health status-QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. High scale score=higher response level; a high score for a functional scale=a healthy level of function, high score for the global health status/QoL=high quality of life but a high score for a symptom scale / item=high level of symptomatology/problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations
    End point type
    Secondary
    End point timeframe
    Baseline 12,24,36,48 weeks
    End point values
    		 Week 12 Week 24 Week 36 Week 48
    Number of subjects analysed
    27
    17
    13
    28
    Units: scores
    arithmetic mean (standard deviation)
        Global health status/QoL (27,16,13,26)
    -9 ( 22.04 )
    -3.6 ( 19.71 )
    1.9 ( 16.37 )
    -8.3 ( 22.48 )
        Physical functioning(27,17,13,28)
    -5.1 ( 19.16 )
    -1 ( 14.52 )
    4.9 ( 13.79 )
    -10.8 ( 29.97 )
        Role functioning (26,16,12,27)
    -4.5 ( 33.19 )
    3.1 ( 23.74 )
    8.3 ( 23.03 )
    -12.3 ( 30.52 )
        Emotional functioning(27,16,13,26)
    2.6 ( 21.36 )
    -3.1 ( 14.87 )
    7.5 ( 9.9 )
    0.6 ( 21.59 )
        Cognitive functioning (27,16,13,27)
    -8.6 ( 21.37 )
    -5.2 ( 17.97 )
    1.3 ( 22.01 )
    -3.7 ( 21.35 )
        Social functioning(27,16,13,26)
    -9.9 ( 25 )
    -9.4 ( 24.32 )
    3.8 ( 15.45 )
    -14.7 ( 31.74 )
        Fatigue (27,17,13,28)
    8.6 ( 26.92 )
    9.5 ( 15.93 )
    0.9 ( 16.64 )
    7.3 ( 24.66 )
        Nausea/ vomiting (27,17,13,28)
    -1.2 ( 15.96 )
    2.9 ( 16.91 )
    -3.8 ( 15.45 )
    -2.4 ( 23.88 )
        Pain(27,17,13,28)
    1.2 ( 26.12 )
    3.9 ( 24.67 )
    -1.3 ( 20.93 )
    0.6 ( 24.64 )
        Dyspnea(27,16,13,28)
    18.5 ( 37.36 )
    8.3 ( 25.82 )
    2.6 ( 25.32 )
    10.7 ( 27.3 )
        Insomnia(27,17,13,28)
    3.7 ( 26.69 )
    2 ( 29.98 )
    0 ( 23.57 )
    -3.6 ( 37.78 )
        Appetite loss(27,17,13,28)
    30.9 ( 40.22 )
    23.5 ( 28.3 )
    12.8 ( 28.99 )
    16.7 ( 35.72 )
        Constipation(27,17,13,28)
    4.9 ( 32.95 )
    11.8 ( 28.73 )
    10.3 ( 21.01 )
    8.3 ( 19.51 )
        Diarrhea(27,16,13,27)
    4.9 ( 25.66 )
    8.3 ( 37.52 )
    -5.1 ( 22.96 )
    7.4 ( 28.24 )
        Financial problems (27,16,13,26)
    -1.2 ( 21.64 )
    -10.4 ( 26.44 )
    -10.3 ( 21.01 )
    -2.6 ( 18.67 )
    No statistical analyses for this end point

    Secondary: Percentage of patient responses in EuroQoL 5-dimension questionnaire - FAS

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    End point title
    		 Percentage of patient responses in EuroQoL 5-dimension questionnaire - FAS
    End point description
    The EQ-5D is a standardized instrument to assess health state values that has been developed, validated and published by the EuroQol Group (EuroQol Group 1990). The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system comprises of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Percentage of participants' responses were presented by visits. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations.
    End point type
    Secondary
    End point timeframe
    Baseline 12,24,36,48 weeks
    End point values
    		 Day 1 Week 12 Week 24 Week 36 Week 48
    Number of subjects analysed
    49
    49
    49
    49
    49
    Units: Percentage of participants
    number (not applicable)
        Mobility-no problem
    38.8
    20.4
    18.4
    14.3
    16.3
        Mobility-slight problem
    18.4
    14.3
    10.2
    8.2
    16.3
        Mobility-moderate problem
    32.7
    20.4
    8.2
    2
    14.3
        Mobility-severe problem
    6.1
    2
    0
    2
    6.1
        Mobility-unable to walk
    0
    0
    0
    0
    4.1
        Self-care - no problem
    69.4
    44.9
    34.7
    24.5
    40.8
        Self-care - slight problem
    18.4
    4.1
    0
    0
    10.2
        Self-care - moderate problem
    6.1
    8.2
    2
    2
    4.1
        Self-care -severe problem
    2
    0
    0
    0
    2
        Self-care - unable
    0
    0
    0
    0
    0
        Usual activities - no problems
    30.6
    14.3
    22.4
    14.3
    18.4
        Usual activities - slight problems
    22.4
    16.3
    2
    8.2
    14.3
        Usual activities - moderate problems
    28.6
    22.4
    12.2
    2
    12.2
        Usual activities - severe problems
    10.2
    4.1
    0
    2
    6.1
        Usual activities -unable to do
    4.1
    0
    0
    0
    6.1
        Pain/discomfort - none
    20.4
    14.3
    10.2
    12.2
    18.4
        Pain/discomfort - slight
    30.6
    16.3
    18.4
    8.2
    20.4
        Pain/discomfort - moderate
    40.8
    22.4
    8.2
    6.1
    14.3
        Pain/discomfort - severe
    4.1
    4.1
    0
    0
    4.1
        Pain/discomfort - extreme
    0
    0
    0
    0
    0
        Anxiety/depression - none
    44.9
    22.4
    18.4
    16.3
    22.4
        Anxiety/depression - slight
    34.7
    22.4
    12.2
    10.2
    20.4
        Anxiety/depression - moderate
    16.3
    12.2
    6.1
    0
    8.2
        Anxiety/depression - severe
    0
    0
    0
    0
    6.1
        Anxiety/depression - extreme
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in EuroQoL 5-dimension visual analogue scores - FAS

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    End point title
    		 Change from baseline in EuroQoL 5-dimension visual analogue scores - FAS
    End point description
    The EQ-5D is another standardized instrument to assess health state values that has been developed, validated and published by the EuroQol Group (EuroQol Group 1990). The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system comprises of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The change in EuroQoL EQ-5D overall health state (VAS), from baseline to each post-baseline time point was described with the mean, and 95% CI of the mean. Results should be interpreted with caution as the numbers of patients with available data over time were limited, and because of high variances as evidenced by large standard deviations.
    End point type
    Secondary
    End point timeframe
    Baseline 12,24,36,48 weeks
    End point values
    		 Week 12 Week 24 Week 36 Week 48
    Number of subjects analysed
    25
    16
    12
    27
    Units: scores
        arithmetic mean (standard deviation)
    -7.9 ( 18.98 )
    -6.1 ( 12.47 )
    -6.3 ( 10.03 )
    -11.6 ( 22.58 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Everolimus + Exemestane
    Reporting group description
    		 Everolimus + Exemestane

    Serious adverse events
    		 Everolimus + Exemestane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 49 (44.90%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiogenic pulmonary oedema
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus + Exemestane
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 49 (100.00%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Blood cholesterol increased
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Weight decreased
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    6
    Blood creatinine increased
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    6
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    7
    Headache
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Anaemia
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    11
    General disorders and administration site conditions
    Axillary pain
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    22 / 49 (44.90%)
         occurrences all number
    23
    Mucosal inflammation
         subjects affected / exposed
    17 / 49 (34.69%)
         occurrences all number
    18
    Oedema peripheral
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Peripheral swelling
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Abdominal pain
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    9
    Diarrhoea
         subjects affected / exposed
    22 / 49 (44.90%)
         occurrences all number
    27
    Mouth ulceration
         subjects affected / exposed
    11 / 49 (22.45%)
         occurrences all number
    16
    Dyspepsia
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5
    Dry mouth
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    14 / 49 (28.57%)
         occurrences all number
    15
    Oral pain
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    7
    Stomatitis
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    8
    Vomiting
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 49 (36.73%)
         occurrences all number
    19
    Dyspnoea
         subjects affected / exposed
    11 / 49 (22.45%)
         occurrences all number
    14
    Epistaxis
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    8
    Oropharyngeal pain
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Productive cough
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Pneumonitis
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    18 / 49 (36.73%)
         occurrences all number
    20
    Pruritus
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    6
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    7
    Arthralgia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    5
    Joint swelling
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    7
    Musculoskeletal pain
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    6
    Oral candidiasis
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 49 (32.65%)
         occurrences all number
    18
    Hyperglycaemia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Hypercalcaemia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2013
    Post-trial treatment was to be captured for all patients when they completed the trial, whether they withdrew early or completed the full treatment duration. All new anticancer therapies given after the last dose of the study drug were to be recorded on CRF pages designed to capture antineoplastic therapies. An interim analysis was included on all patients who commenced treatment in the study by 04-Sep-2013. This first interim analysis included all screening and baseline data. A second interim analysis was planned to be performed after all patients completed 24 weeks of treatment (or prematurely discontinued on or before this time). End of study was extended from Week 48 until patients progressed.

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

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