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    Clinical Trial Results:
    CORALLEEN: A Phase 2 Clinical Trial of multi-agent Chemotherapy or letrozole plus Ribociclib (LEE001) as neoadjuvant treatment for postmenopausal patients with Luminal B/HER2-negative breast cancer.

    Summary
    EudraCT number
    2016-003098-17
    Trial protocol
    ES  
    Global end of trial date
    01 Jul 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Apr 2022
    First version publication date
    27 Apr 2022
    Other versions
    Summary report(s)
    SOLTI-1402_SYNOPSIS CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    SOLTI-1402
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03248427
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    SOLTI
    Sponsor organisation address
    C/ Balmes 89 3-7, Barcelona, Spain, 08008
    Public contact
    Investigación Clínica, SOLTI, 34 933436302, regsolti@gruposolti.org
    Scientific contact
    Investigación Clínica, SOLTI, 34 933436302, regsolti@gruposolti.org
    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
    08 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the clinical benefit of ribociclib plus letrozole versus chemotherapy.
    Protection of trial subjects
    All patients received written and verbal information regarding the study at a prior interview with investigator site staff. This information will emphasised that participation in the study is voluntary and that the subject may withdraw from the study at any time and for any reason. All patients were given the opportunity to ask questions about the study and were given sufficient time to decide whether to participate.The IC mentioned which specific data was recorded, collected, processed and could be transferred to European Economic Area (EEA) or non-EEA countries. Personal data was managed in accordance with the applicable legislation in force at the time, and in particular, in accordance with Regulation (EU) No 2016/679 of 27 April 2016 on the protection of individuals with regard to the processing of their personal data (hereinafter, “GDPR”). A copy of the patient information including the signed IC form was provided to the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jul 2017
    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
    Spain: 106
    Worldwide total number of subjects
    106
    EEA total number of subjects
    106
    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)
    53
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Planned: 94 patients to be recruited. Considering 10% drop-out rate, 104 patients was planned to be included.From July 27, 2017 to December 7, 2018, 198 patients were assessed for eligibility across 21 centres in Spain and 106 were finally recruited.

    Pre-assignment
    Screening details
    Postmenopausal women with untreated primary operable Hormone receptor positive (HR+)/HER2-negative Luminal B breast cancer according to PAM50 intrinsic subtype

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    letrozole plus ribociclib
    Arm description
    The letrozole plus ribociclib treatment consisted of six 28-days cycles of daily letrozole (2.5mg; continuous) and ribociclib (600mg; 3-weeks-on/-week-off). The study investigational treatment was Ribociclib (Kisqali ®) provided by Novartis. It was administered as a flat-fixed dose of 600 mg daily (three 200-mg capsules), days 1 to 21 of a 28-days cycle. Letrozole (Femara®) was also supplied by Novartis. Letrozole was administered orally, once per day, days 1 to 28 of a 28 days cycle, at 2.5 mg. Both ribociclib and letrozole were administered orally during 6 cycles and independently of the body surface area or body weight. The ribociclib destined for use in the trial came from batches 1010010567 and WX027; and letrozole from batch SH083
    Arm type
    Experimental

    Investigational medicinal product name
    Ribociclib (Kisqali®)
    Investigational medicinal product code
    L01EF02
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib was administered as a flat-fixed dose of 600 mg daily (three 200-mg capsules), days 1 to 21 of a 28-days cycle during 6 cycles.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    L02BG04
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole (Femara®) was also supplied by Novartis. Letrozole was administered once per day, days 1 to 28 of a 28 days cycle, at 2.5 mg.

    Arm title
    Chemotherapy
    Arm description
    The chemotherapy treatment consisted of four cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every21 days) followed by weekly paclitaxel during 12 weeks. In total, neoadjuvant therapy lasted for 24 weeks in each arm.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    letrozole plus ribociclib Chemotherapy
    Started
    52
    54
    Completed
    43
    42
    Not completed
    9
    12
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    8
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    letrozole plus ribociclib
    Reporting group description
    The letrozole plus ribociclib treatment consisted of six 28-days cycles of daily letrozole (2.5mg; continuous) and ribociclib (600mg; 3-weeks-on/-week-off). The study investigational treatment was Ribociclib (Kisqali ®) provided by Novartis. It was administered as a flat-fixed dose of 600 mg daily (three 200-mg capsules), days 1 to 21 of a 28-days cycle. Letrozole (Femara®) was also supplied by Novartis. Letrozole was administered orally, once per day, days 1 to 28 of a 28 days cycle, at 2.5 mg. Both ribociclib and letrozole were administered orally during 6 cycles and independently of the body surface area or body weight. The ribociclib destined for use in the trial came from batches 1010010567 and WX027; and letrozole from batch SH083

    Reporting group title
    Chemotherapy
    Reporting group description
    The chemotherapy treatment consisted of four cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every21 days) followed by weekly paclitaxel during 12 weeks. In total, neoadjuvant therapy lasted for 24 weeks in each arm.

    Reporting group values
    letrozole plus ribociclib Chemotherapy Total
    Number of subjects
    52 54 106
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    The baseline median age was 63.5 years (range 49-79)
    Units: years
        median (full range (min-max))
    63 (50 to 78) 64 (49 to 79) -
    Gender categorical
    Units: Subjects
        Female
    52 54 106
        Male
    0 0 0
    Tumor size
    Units: Subjects
        T1
    3 3 6
        T2
    40 43 83
        T3
    9 8 17
    Lymph node status
    Units: Subjects
        N0
    31 31 62
        N1
    19 22 41
        N2
    2 1 3
    Histological type
    Units: Subjects
        Ductal
    41 48 89
        Lobular
    10 6 16
        Other
    1 0 1
    Clinical baseline tumour stage
    Units: Subjects
        One
    2 2 4
        Two
    43 45 88
        Three
    7 7 14
    PR expression > 20%
    Units: Subjects
        PR expression >20%
    18 16 34
        PR expression < 20 %
    34 38 72
    Ki67 expression (local)
    Units: Subjects
        ≤14%
    3 2 5
        >14%
    49 51 100
        Missing
    0 1 1
    PR-negative
    Units: Subjects
        PR-negative
    11 9 20
        Other
    41 45 86
    Median ROR score
    Units: Range
        median (full range (min-max))
    70 (52 to 93) 77 (51 to 97) -
    Mean ROR score
    Units: Mean
        arithmetic mean (standard deviation)
    71.5 ± 9.85 74.2 ± 10.7 -
    Ki67 expression mean
    Units: Mean
        arithmetic mean (standard deviation)
    31.1 ± 13.64 35.2 ± 12.6 -
    Ki67 expression (range)
    Units: Median
        median (full range (min-max))
    30 (5 to 75) 35 (12 to 70) -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population was defined as all randomized patients

    Subject analysis set title
    modified ITT (mITT) population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified ITT (mITT) population was defined as all randomized patients who received study medication and had a baseline efficacy measurement and at least one corresponding postbaseline efficacy measurement (for the main efficacy variable).

    Subject analysis set title
    Per Protocol (PP) population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol (PP) population was defined as all randomized subjects who met the inclusion criteria, received study medication, had a baseline efficacy measurement and at least one corresponding post-baseline efficacy measurement (for the main efficacy variable) and did not present major violations of the protocol.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population defined as all randomized subjects who took at least one dose of the study medication

    Subject analysis sets values
    ITT population modified ITT (mITT) population Per Protocol (PP) population Safety population
    Number of subjects
    103
    101
    88
    103
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    The baseline median age was 63.5 years (range 49-79)
    Units: years
        median (full range (min-max))
    63.5 (49 to 79)
    Gender categorical
    Units: Subjects
        Female
    106
        Male
    0
    Tumor size
    Units: Subjects
        T1
    6
        T2
    83
        T3
    17
    Lymph node status
    Units: Subjects
        N0
    62
        N1
    41
        N2
    3
    Histological type
    Units: Subjects
        Ductal
    89
        Lobular
    16
        Other
    1
    Clinical baseline tumour stage
    Units: Subjects
        One
    4
        Two
    88
        Three
    14
    PR expression > 20%
    Units: Subjects
        PR expression >20%
    34
        PR expression < 20 %
    Ki67 expression (local)
    Units: Subjects
        ≤14%
    5
        >14%
    100
        Missing
    1
    PR-negative
    Units: Subjects
        PR-negative
        Other
    Median ROR score
    Units: Range
        median (full range (min-max))
    74.5 (51 to 97)
    Mean ROR score
    Units: Mean
        arithmetic mean (standard deviation)
    72.9 ± 10.3
    ±
    ±
    ±
    Ki67 expression mean
    Units: Mean
        arithmetic mean (standard deviation)
    33.1 ± 13.2
    ±
    ±
    ±
    Ki67 expression (range)
    Units: Median
        median (full range (min-max))
    32 (5 to 75)

    End points

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    End points reporting groups
    Reporting group title
    letrozole plus ribociclib
    Reporting group description
    The letrozole plus ribociclib treatment consisted of six 28-days cycles of daily letrozole (2.5mg; continuous) and ribociclib (600mg; 3-weeks-on/-week-off). The study investigational treatment was Ribociclib (Kisqali ®) provided by Novartis. It was administered as a flat-fixed dose of 600 mg daily (three 200-mg capsules), days 1 to 21 of a 28-days cycle. Letrozole (Femara®) was also supplied by Novartis. Letrozole was administered orally, once per day, days 1 to 28 of a 28 days cycle, at 2.5 mg. Both ribociclib and letrozole were administered orally during 6 cycles and independently of the body surface area or body weight. The ribociclib destined for use in the trial came from batches 1010010567 and WX027; and letrozole from batch SH083

    Reporting group title
    Chemotherapy
    Reporting group description
    The chemotherapy treatment consisted of four cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every21 days) followed by weekly paclitaxel during 12 weeks. In total, neoadjuvant therapy lasted for 24 weeks in each arm.

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population was defined as all randomized patients

    Subject analysis set title
    modified ITT (mITT) population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified ITT (mITT) population was defined as all randomized patients who received study medication and had a baseline efficacy measurement and at least one corresponding postbaseline efficacy measurement (for the main efficacy variable).

    Subject analysis set title
    Per Protocol (PP) population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol (PP) population was defined as all randomized subjects who met the inclusion criteria, received study medication, had a baseline efficacy measurement and at least one corresponding post-baseline efficacy measurement (for the main efficacy variable) and did not present major violations of the protocol.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population defined as all randomized subjects who took at least one dose of the study medication

    Primary: To evaluate the ability of each treatment strategy to provide ROR-low score at surgery

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    End point title
    To evaluate the ability of each treatment strategy to provide ROR-low score at surgery
    End point description
    The primary endpoint was to evaluate the rate of ROR-low disease after neoadjuvant treatment (i.e. at surgery) according to the standardized PAM50 assay. ROR score is based on information coming from gene expression data and tumour size and has a range from 0 to 100. ROR-low disease was defined as ≤40 points if node-negative and ≤15 points if 1-3 positive nodes. ROR-intermediate disease was defined as 41-60 points if node-negative and 16-40 points if 1-3 positive nodes. ROR-high disease was defined as 61-100 points if node-negative and 41-100 points if 1-3 positive nodes. All patients with ≥4 node positives were considered ROR-high risk regardless of ROR score.
    End point type
    Primary
    End point timeframe
    ROR score was determined at surgery
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Subjects
        ROR-low disease
    23
    24
        ROR-intermediate disease
    15
    16
        ROR-high disease
    11
    11
        Missing
    0
    1
    Statistical analysis title
    Estimation of ROR-low rates
    Statistical analysis description
    Main analysis is the estimation of ROR-low rates and was described by means of difference of proportions and 95% confidence interval using exact methods based on binomial, ClopperPearson method independently in both treatments groups. This analysis was performed using ITT approach on ADO data. This primary efficacy analysis was also analyzed using the PP set to test the robustness of the results with the same approach (ADO data)
    Comparison groups
    letrozole plus ribociclib v Chemotherapy
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    ≤ 0.05 [1]
    Method
    Clopper-Pearson
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [1] - All statistical tests were applied with a 0.05 two-sided significance level.

    Secondary: Ki67 (central)

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    End point title
    Ki67 (central)
    End point description
    Consistent with the primary results were the results obtained with Ki67 at surgery (Table 10). The correlation coefficients between ROR score at surgery (as a continuous variable) and Ki67 immunohistochemistry (IHC) expression was 15.4 in the chemotherapy arm and 8.4 in the ribociclib plus letrozole arm.
    End point type
    Secondary
    End point timeframe
    At surgery
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Ki67 immunohistochemistry (IHC) express
        median (full range (min-max))
    3 (1 to 70)
    10 (1 to 90)
    No statistical analyses for this end point

    Secondary: Ki67 (central)

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    End point title
    Ki67 (central)
    End point description
    End point type
    Secondary
    End point timeframe
    At surgery
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Ki67 immunohistochemistry (IHC) express
        arithmetic mean (standard deviation)
    8.4 ± 13.6
    15.4 ± 17.3
    No statistical analyses for this end point

    Secondary: ORR by MRI

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    End point title
    ORR by MRI
    End point description
    ORR by physical examination, mammography and breast US, if available. Clinical response was evaluated. All patients who have received at least one treatment and have their disease re-evaluated, either by physical examination, US or by MRI, was assigned a response category according to RECIST 1.1 (CR, PR, SD or PD). Tumor overall objective response rate (ORR) was defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Breast MRI at screening period and pre-surgery visit at the end of the neoadjuvant treatment
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Subjects
        CR
    7
    10
        PR
    21
    31
        SD
    16
    7
        PD
    0
    0
        NA
    5
    3
    No statistical analyses for this end point

    Secondary: ORR by physical examination

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    End point title
    ORR by physical examination
    End point description
    ORR by physical examination, mammography and breast US, if available. Clinical response was evaluated. All patients who have received at least one treatment and have their disease re-evaluated, either by physical examination, US or by MRI, was assigned a response category according to RECIST 1.1 (CR, PR, SD or PD).
    End point type
    Secondary
    End point timeframe
    At screening visit and pre-surgery visit at the end of the neoadjuvant treatment
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Subjects
        CR
    16
    16
        PR
    15
    12
        SD
    8
    5
        PD
    1
    3
        NA
    9
    16
    No statistical analyses for this end point

    Secondary: Rate of pCR

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    End point title
    Rate of pCR
    End point description
    pCR in the breast and pCR in the breast and axillary lymph nodes at surgery. Rate of pCR after neaodjuvant treatment. Pathological complete response (pCR) was evaluated in local laboratories according to two different criteria: - pCRB defined as the complete absence of invasive cancer in the breast at the time of the definitive surgery, regardless of axillary status or presence of carcinoma in situ (CIS), according to the NSABP definition and guidelines (ypT0/Tis). The presence or absence of CIS was documented. - pCRBL defined as the complete absence of invasive cancer in the breast and lymph nodes at the time of the definitive surgery (ypT0/Tis, ypN0).
    End point type
    Secondary
    End point timeframe
    at surgery
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Subjects
        Yes
    0
    3
    No statistical analyses for this end point

    Secondary: Residual Cancer Burden (RCB)

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    End point title
    Residual Cancer Burden (RCB)
    End point description
    End point type
    Secondary
    End point timeframe
    At surgery
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Subjects
        0-1
    3
    6
        II-III
    46
    45
    No statistical analyses for this end point

    Secondary: Preoperative endocrine prognostic index (PEPI) score

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    End point title
    Preoperative endocrine prognostic index (PEPI) score
    End point description
    Preoperative endocrine prognostic index (PEPI) score in the ribociclib plus letrozole treatment arm compared to historical values. In addition, the PEPI score of surgery samples was determined in patients assigned to the ribociclib-letrozole treatment arm, comparing them to historical values of neoadjuvant letrozole treatment. Both assessments were performed in the central laboratory.
    End point type
    Secondary
    End point timeframe
    Preoperative and surgery samples
    End point values
    letrozole plus ribociclib Chemotherapy
    Number of subjects analysed
    49
    52
    Units: Subjects
        zero
    11
    9
        1-3
    25
    24
        >4
    13
    17
        Missing
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessment of adverse events and general safety was collected at post-surgery visit. Patients withdrawn from the study before surgery attended to a last follow-up visit 30 days after the administration of the last treatment dose.
    Adverse event reporting additional description
    Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 4.03, including dose reductions, delays and treatment discontinuations.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    letrozole plus ribociclib
    Reporting group description
    The letrozole plus ribociclib treatment consisted of six 28-days cycles of daily letrozole (2.5mg; continuous) and ribociclib (600mg; 3-weeks-on/-week-off). The study investigational treatment was Ribociclib (Kisqali ®) provided by Novartis. It was administered as a flat-fixed dose of 600 mg daily (three 200-mg capsules), days 1 to 21 of a 28-days cycle. Letrozole (Femara®) was also supplied by Novartis. Letrozole was administered orally, once per day, days 1 to 28 of a 28 days cycle, at 2.5 mg. Both ribociclib and letrozole were administered orally during 6 cycles and independently of the body surface area or body weight. The ribociclib destined for use in the trial came from batches 1010010567 and WX027; and letrozole from batch SH083

    Reporting group title
    Chemotherapy
    Reporting group description
    The chemotherapy treatment consisted of four cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every21 days) followed by weekly paclitaxel during 12 weeks. In total, neoadjuvant therapy lasted for 24 weeks in each arm.

    Serious adverse events
    letrozole plus ribociclib Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 51 (3.92%)
    8 / 52 (15.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    6 / 52 (11.54%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung abscess
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    letrozole plus ribociclib Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 51 (100.00%)
    52 / 52 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 52 (3.85%)
         occurrences all number
    3
    3
    Venous thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    13 / 51 (25.49%)
    28 / 52 (53.85%)
         occurrences all number
    18
    43
    Axillary pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Extravasation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    7 / 51 (13.73%)
    10 / 52 (19.23%)
         occurrences all number
    11
    32
    Hot flush
         subjects affected / exposed
    7 / 51 (13.73%)
    0 / 52 (0.00%)
         occurrences all number
    8
    0
    Influenza like illness
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Medical device site erythema
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Mucosal dryness
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 52 (5.77%)
         occurrences all number
    6
    4
    Mucosal inflammation
         subjects affected / exposed
    5 / 51 (9.80%)
    18 / 52 (34.62%)
         occurrences all number
    6
    31
    Oedema peripheral
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    4
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Adnexa uteri pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Breast pain
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 52 (1.92%)
         occurrences all number
    2
    1
    Dysmenorrhoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal dryness
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 52 (7.69%)
         occurrences all number
    6
    5
    Dysphonia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 52 (3.85%)
         occurrences all number
    2
    2
    Epistaxis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Nasal dryness
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Nasal inflammation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    5
    Productive cough
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 52 (7.69%)
         occurrences all number
    5
    5
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    2
    1
    Depression
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 51 (3.92%)
    6 / 52 (11.54%)
         occurrences all number
    2
    7
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 51 (25.49%)
    4 / 52 (7.69%)
         occurrences all number
    35
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 51 (21.57%)
    5 / 52 (9.62%)
         occurrences all number
    20
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Blood cholesterol increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    3
    Blood creatine increased
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Blood phosphorus increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    2
    Lipase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    11 / 51 (21.57%)
    16 / 52 (30.77%)
         occurrences all number
    33
    26
    Platelet count decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Platelet count increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Transaminases increased
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0
    Weight decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    4 / 51 (7.84%)
    5 / 52 (9.62%)
         occurrences all number
    8
    10
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    6
    Headache
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 52 (5.77%)
         occurrences all number
    6
    5
    Hypoaesthesia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 51 (1.96%)
    21 / 52 (40.38%)
         occurrences all number
    1
    27
    Neurotoxicity
         subjects affected / exposed
    0 / 51 (0.00%)
    10 / 52 (19.23%)
         occurrences all number
    0
    17
    Paraesthesia
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Presyncope
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    2
    Vertigo
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 51 (7.84%)
    18 / 52 (34.62%)
         occurrences all number
    7
    28
    Febrile neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    7 / 52 (13.46%)
         occurrences all number
    0
    9
    Leukopenia
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 52 (3.85%)
         occurrences all number
    5
    2
    Neutropenia
         subjects affected / exposed
    17 / 51 (33.33%)
    19 / 52 (36.54%)
         occurrences all number
    69
    29
    Thrombocytopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    1
    Tinnitus
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Dry eye
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Hordeolum
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Keratitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 52 (3.85%)
         occurrences all number
    1
    2
    Vision blurred
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Xerophthalmia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 52 (3.85%)
         occurrences all number
    6
    3
    Abdominal pain lower
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4
    Anal fissure
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Colitis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    6 / 51 (11.76%)
    13 / 52 (25.00%)
         occurrences all number
    7
    22
    Dental caries
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    7 / 51 (13.73%)
    14 / 52 (26.92%)
         occurrences all number
    16
    19
    Dry mouth
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 52 (9.62%)
         occurrences all number
    2
    7
    Dysgeusia
         subjects affected / exposed
    2 / 51 (3.92%)
    14 / 52 (26.92%)
         occurrences all number
    2
    17
    Dyspepsia
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 52 (7.69%)
         occurrences all number
    5
    6
    Dysphagia
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    2
    Haemorrhoids
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Odynophagia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Oesophagitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    0
    7
    Vomiting
         subjects affected / exposed
    2 / 51 (3.92%)
    9 / 52 (17.31%)
         occurrences all number
    2
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 51 (23.53%)
    33 / 52 (63.46%)
         occurrences all number
    12
    43
    Dermatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    5
    Eczema
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Erythema
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences all number
    1
    4
    Hand dermatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Nail discolouration
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4
    Nail dystrophy
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Nail infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Nail toxicity
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    0
    5
    Onycholysis
         subjects affected / exposed
    1 / 51 (1.96%)
    11 / 52 (21.15%)
         occurrences all number
    1
    12
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Pruritus
         subjects affected / exposed
    8 / 51 (15.69%)
    4 / 52 (7.69%)
         occurrences all number
    9
    6
    Rash
         subjects affected / exposed
    12 / 51 (23.53%)
    10 / 52 (19.23%)
         occurrences all number
    17
    11
    Rash maculo-papular
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Scar pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Skin fissures
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Skin reaction
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    1
    Toxic skin eruption
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 52 (3.85%)
         occurrences all number
    2
    2
    Urticaria
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Micturition urgency
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Polyuria
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 52 (0.00%)
         occurrences all number
    5
    0
    Back pain
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Bone pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Flank pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    7 / 51 (13.73%)
    4 / 52 (7.69%)
         occurrences all number
    8
    5
    Myalgia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Neck pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    Sciatica
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Cellulitis
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Gingivitis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Herpes ophthalmic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Infected seroma
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Lip infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Lung abscess
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Mastitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Vulvitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Wound infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Cell death
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    4 / 51 (7.84%)
    11 / 52 (21.15%)
         occurrences all number
    4
    17
    Dehydration
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Apr 2017
    Amendment number 1 to the protocol (versión 2.0 27 Apr 2017) The amendment consisted of: 1) The addition of plasma sample collection for biomarker analyses Due to the prevalence of the mutations measured at baseline and post treatment and the leves of ctDNA measured in three time.points may provide information on response or resistance to therapy. 2) Expansion to the number of sites: one site was added. 3) Corrections and minor changes 4) Update in the background in reference to clinical trials (MONALEESA 2) 5) Unification of the Prescreening with the Main Informed Consent
    15 Jun 2018
    Amendment number 2 to the protocol (Version 3.0 15 June 2018) 1) Change of primary objective and endpoint of the study. 2) Clarify and/or amend of the secondary objectives/endpoints. 3) Clarify/amend some analytical determinations and procedures during the study. 4) Clarify/amend procedures and timelines in Schedule of assessments, especially in reference to the window of collection of tumor sample, randomization and between last dose of ribociclib and surgery. 5) Minor changes as grammatical, typographical and administrative corrections, as well as the addition of new references.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/31838010
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