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    Clinical Trial Results:
    A randomized pre-surgical pharmacodynamics study to assess the biological activity of LEE011 plus letrozole versus single agent letrozole in primary breast cancer (MONALEESA-1)

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2013-002588-24
    Trial protocol
    		 NL   ES   FR  
    Global end of trial date
    10 Sep 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Aug 2016
    First version publication date
    12 Jun 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CLEE011A2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01919229
    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 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    10 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To estimate the difference in anti-proliferative activity of ribociclib 600 mg once daily and ribociclib 400 mg once daily in combination with letrozole 2.5 mg once daily vs. single agent letrozole 2.5 mg once daily as measured by changes in levels of the proliferative marker Ki67 from Baseline to time of surgery (Day 15).
    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
    10 Oct 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
    Spain: 6
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    14
    EEA total number of subjects
    6
    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)
    7
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 20 patients were screened, of those 14 patients completed the Screening phase and were randomized. 6 patients discontinued during the Screening phase; 3 patients were considered screen failure and 3 patients discontinued due to patient’s decision.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Letrozole
    Arm description
    		 Letrozole 2.5 mg alone once daily
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was supplied in 2.5mg tablets for oral use

    Arm title
    		 LEE011 400mg + letrozole
    Arm description
    		 Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was supplied in 2.5mg tablets for oral use

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    LEE011
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib was supplied in 200 mg hard gelatin capsules for oral use.

    Arm title
    		 LEE011 600mg + letrozole
    Arm description
    		 Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    LEE011
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib was supplied in 200 mg hard gelatin capsules for oral use.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was supplied in 2.5mg tablets for oral use

    Number of subjects in period 1
    		Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Started
    4
    6
    4
    Completed
    4
    6
    3
    Not completed
    0
    0
    1
         Subject/guardian decision
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Letrozole
    Reporting group description
    		 Letrozole 2.5 mg alone once daily

    Reporting group title
    LEE011 400mg + letrozole
    Reporting group description
    		 Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.

    Reporting group title
    LEE011 600mg + letrozole
    Reporting group description
    		 Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.

    Reporting group values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole Total
    Number of subjects
    		 4 6 4 14
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 3 0 7
        From 65-84 years
    		 0 3 4 7
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 57 ( 5.48 ) 64.2 ( 9.91 ) 70 ( 4.24 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 4 6 4 14
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Letrozole
    Reporting group description
    		 Letrozole 2.5 mg alone once daily

    Reporting group title
    LEE011 400mg + letrozole
    Reporting group description
    		 Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.

    Reporting group title
    LEE011 600mg + letrozole
    Reporting group description
    		 Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.

    Primary: Cell cycle response rate per cell proliferation marker Ki67

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    End point title
    		 Cell cycle response rate per cell proliferation marker Ki67 [1]
    End point description
    Cell cycle response rate is defined by percentage of patients with natural logarithm of Ki-67 levels (expressed as percentage of baseline values) of less than 1 at the time of surgery. Since the trial was prematurely terminated, no statistical analysis was done.
    End point type
    Primary
    End point timeframe
    Day 1, Day15
    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: Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Percentage of positive cells for Ki67
        number (not applicable)
    Notes
    [2] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [3] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [4] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    No statistical analyses for this end point

    Secondary: Safety and tolerability of the combination

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    End point title
    		 Safety and tolerability of the combination
    End point description
    Occurrence, frequency and severity of adverse events (AEs), laboratory abnormalities
    End point type
    Secondary
    End point timeframe
    Up to 30 days after the last dose
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    4
    6
    4
    Units: patients
        Adverse Events
    0
    0
    0
        Serious Adverse Events
    0
    0
    0
        Death
    0
    0
    0
        Other Adverse Events
    2
    5
    4
    No statistical analyses for this end point

    Secondary: Change from baseline in electrocardiogram (ECG) parameters

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    End point title
    		 Change from baseline in electrocardiogram (ECG) parameters
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Day 14
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: milliseconds
        least squares mean (standard error)
    ( )
    ( )
    ( )
    Notes
    [5] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [6] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [7] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    No statistical analyses for this end point

    Secondary: Change from baseline in expression of Retinoblastoma Protein (pRB)

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    End point title
    		 Change from baseline in expression of Retinoblastoma Protein (pRB)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: unit on scale
        least squares mean (standard error)
    ( )
    ( )
    ( )
    Notes
    [8] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [9] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [10] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    No statistical analyses for this end point

    Secondary: PK (pharmacokinetics) parameters, including but not limited to, Cmax, Tmax, AUClast for LEE011 (and any relevant metabolites) and letrozole.

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    End point title
    		 PK (pharmacokinetics) parameters, including but not limited to, Cmax, Tmax, AUClast for LEE011 (and any relevant metabolites) and letrozole.
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1, 8, 14 and 15
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: ng/mL
    Notes
    [11] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [12] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [13] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    No statistical analyses for this end point

    Secondary: Change in ECG morphology

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    End point title
    		 Change in ECG morphology
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Day 14
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: milliseconds
    Notes
    [14] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [15] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [16] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    No statistical analyses for this end point

    Secondary: Correlation between PK concentrations and ECG changes

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    End point title
    		 Correlation between PK concentrations and ECG changes
    End point description
    Correlation between the QTc interval change from baseline and plasma concentrations of LEE011 and/or any relevant metabolites
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: ratio
    Notes
    [17] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [18] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [19] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    No statistical analyses for this end point

    Secondary: Change from baseline in expression of Cyclin-Dependent Kinase 1 (CDK1)

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    End point title
    		 Change from baseline in expression of Cyclin-Dependent Kinase 1 (CDK1)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15
    End point values
    		 Letrozole LEE011 400mg + letrozole LEE011 600mg + letrozole
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    Units: percentage
    Notes
    [20] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [21] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    [22] - Trial was terminated with only a few patients enrolled. Hence no statistical analysis was done
    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
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Letrozole
    Reporting group description
    		 Letrozole 2.5 mg alone once daily

    Reporting group title
    LEE 600mg
    Reporting group description
    		 Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.

    Reporting group title
    LEE 400mg
    Reporting group description
    		 Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.

    Serious adverse events
    		 Letrozole LEE 600mg LEE 400mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Letrozole LEE 600mg LEE 400mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 4 (100.00%)
    5 / 6 (83.33%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    LIPASE INCREASED
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    PROCEDURAL PAIN
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    SEROMA
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    2
    FATIGUE
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    PYREXIA
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    DIARRHOEA
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    DYSPEPSIA
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    NAUSEA
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 4 (75.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    STOMATITIS
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    VOMITING
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    HERPES ZOSTER
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    POST PROCEDURAL INFECTION
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2014
    The purpose of amendment 1 was to clarify some of the study assessments required in the protocol and to take into consideration differences in local practice at the study centers, based on consultation with the study steering committee and feedback received from participating centers’ IRBs/IECs and Health Authorities. The amendment also included an update of nonclinical and clinical data for ribociclib alone and in combination with letrozole.

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

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