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    Clinical Trial Results:
    A phase Ib/II, multicenter, study of LEE011 in combination with LGX818 in adult patients with BRAF mutant melanoma

    Summary
    EudraCT number
    		 2012-004551-36
    Trial protocol
    		 IT   ES   DE   NL   GB  
    Global end of trial date
    13 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Apr 2016
    First version publication date
    29 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLEE011X2105
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01777776
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Array BioPharma, Inc.
    Sponsor organisation address
    1865 33rd Street, Boulder, United States, 80301
    Public contact
    Clinical Operations, Array BioPharma, Inc., 1 303-381-6604, info@arraybiopharma.com
    Scientific contact
    Clinical Operations, Array BioPharma, Inc., 1 303-381-6604, info@arraybiopharma.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
    13 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase Ib: • To estimate the MTD(s) and/or RP2D of oral ribociclib in combination with oral encorafenib in patients with BRAF mutant melanoma. Phase II: • To assess the anti-tumor activity of ribociclib in combination with encorafenib vs. encorafenib alone in patients with metastatic BRAF mutant melanoma who are naïve to prior selective BRAFi treatment. • To assess the anti-tumor activity of ribociclib in combination with encorafenib in patients with metastatic BRAF mutant melanoma who are resistant to prior selective BRAFi treatment. Enrollment in this study was halted during the Phase Ib (dose escalation phase) before the determination of MTD(s)/RP2D. All ongoing patients were followed until discontinuation before the study was terminated. The Phase II part of the study was not initiated. Therefore, all Phase II endpoints are not reported on, as no patients were enrolled in the Phase II part of the study.
    Protection of trial subjects
    This clinical study was designed, shall be implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of Helsinki. Eligible patients were only included in the study after providing written (witnessed, where required by law or regulation), IRB/IEC/REB-approved informed consent. Informed consent was obtained before conducting any study-specific procedures (i.e. all of the procedures described in the protocol). The process of obtaining informed consent was documented in the patient source documents. The date when a patient’s Informed Consent was actually obtained was captured in their Case Report Forms.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    10 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    28
    EEA total number of subjects
    1
    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)
    18
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment to CLEE011X2105 began on 10-July-2013. The study concluded on 13-April-2015. Participant Flow data is comprised of the Full Analysis Set (FAS), which is all patients who received at least one dose of LGX818 or LEE011. Not completed subjects represents subjects that stopped treatment early, due to the corresponding reason.

    Pre-assignment
    Screening details
    		 In response to developments in the treatment of melanoma, the sponsor reviewed the data from the ongoing study and decided to halt further enrollment of patients in the Phase Ib part of the study. Consequently, the Phase II part of the study was not performed. Early termination of the study was not due to any safety concerns.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Blinding implementation details are not applicable, due to study being open-label.

    Arms
    Arm title
    		 Phase I (Dose Escalation)
    Arm description
    		 Adult patients with locally advanced or metastatic BRAF V600 mutant melanoma who are resistant to selective BRAFi treatment or patients who are naïve to selective BRAFi treatment. LEE011: Administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle). LGX818: Administered orally, once daily on a continuous dosing schedule (28-day cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    LEE011
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle).

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, once daily on a continuous dosing schedule (28-day cycle).

    Number of subjects in period 1
    		Phase I (Dose Escalation)
    Started
    28
    Completed
    0
    Not completed
    28
         Consent withdrawn by subject
    1
         Disease progression
    21
         Adverse event, non-fatal
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I (Dose Escalation)
    Reporting group description
    		 Adult patients with locally advanced or metastatic BRAF V600 mutant melanoma who are resistant to selective BRAFi treatment or patients who are naïve to selective BRAFi treatment. LEE011: Administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle). LGX818: Administered orally, once daily on a continuous dosing schedule (28-day cycle).

    Reporting group values
    		 Phase I (Dose Escalation) Total
    Number of subjects
    		 28 28
    Age Categorical
    Units: participants
        <=18 years
    		 0 0
        Between 18 and 65 years
    		 18 18
        >=65 years
    		 10 10
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.6 ( 13.9 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 11 11
        Male
    		 17 17
    WHO/ECOG performance status
    Categories: • 0 - Fully active, able to carry on all pre-disease performance without restriction • 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work • 2 - Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours • 3 - Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours • 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    Units: Subjects
        0:
    		 8 8
        1:
    		 19 19
        2:
    		 1 1
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 79.44 ( 14.45 ) -
    Subject analysis sets

    Subject analysis set title
    Phase Ib: LEE011 200 mg + LGX818 300 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis (FAS) included all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis set title
    Phase Ib: LEE011 300 mg + LGX818 200 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) included all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis set title
    Phase Ib: LEE011 400 mg + LGX818 100 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) includes all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis set title
    Phase Ib: LEE011 400 mg + LGX818 200 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) included all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis sets values
    		 Phase Ib: LEE011 200 mg + LGX818 300 mg (FAS) Phase Ib: LEE011 300 mg + LGX818 200 mg (FAS) Phase Ib: LEE011 400 mg + LGX818 100 mg (FAS) Phase Ib: LEE011 400 mg + LGX818 200 mg (FAS)
    Number of subjects
    6
    12
    6
    4
    Age Categorical
    Units: participants
        <=18 years
    0
    0
    0
    0
        Between 18 and 65 years
    2
    10
    4
    2
        >=65 years
    4
    2
    2
    2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    65 ( 10.71 )
    49.8 ( 13.66 )
    58 ( 10.55 )
    62 ( 17.63 )
    Gender, Male/Female
    Units: participants
        Female
    3
    7
    1
    0
        Male
    3
    5
    5
    4
    WHO/ECOG performance status
    Categories: • 0 - Fully active, able to carry on all pre-disease performance without restriction • 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work • 2 - Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours • 3 - Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours • 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    Units: Subjects
        0:
    2
    4
    1
    1
        1:
    4
    7
    5
    3
        2:
    0
    1
    0
    0
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    84.6 ( 12.793 )
    78.08 ( 17.069 )
    80.17 ( 10.308 )
    74.7 ( 16.415 )

    End points

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    End points reporting groups
    Reporting group title
    Phase I (Dose Escalation)
    Reporting group description
    		 Adult patients with locally advanced or metastatic BRAF V600 mutant melanoma who are resistant to selective BRAFi treatment or patients who are naïve to selective BRAFi treatment. LEE011: Administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle). LGX818: Administered orally, once daily on a continuous dosing schedule (28-day cycle).

    Subject analysis set title
    Phase Ib: LEE011 200 mg + LGX818 300 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis (FAS) included all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis set title
    Phase Ib: LEE011 300 mg + LGX818 200 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) included all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis set title
    Phase Ib: LEE011 400 mg + LGX818 100 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) includes all patients who received at least one dose of encorafenib or ribociclib.

    Subject analysis set title
    Phase Ib: LEE011 400 mg + LGX818 200 mg (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) included all patients who received at least one dose of encorafenib or ribociclib.

    Primary: Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1

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    End point title
    		 Phase Ib - Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 [1]
    End point description
    Dose Limiting Toxicities (DLTs) during the first 28 days of the combination treatment of LEE011 and LGX818. Due to the halt of enrollment, no Maximum Tolerated Dose (MTD) was formally declared during the study.
    End point type
    Primary
    End point timeframe
    Cycle 1 (approximately 28 days)
    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: Not Applicable
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28 [2]
    Units: Not Applicable
    number (not applicable)
        Elevated Bilirubin
    1
        Maculopapular Rash
    1
        Myalagia
    1
        Neuralgia
    1
    Notes
    [2] - Safety Set
    No statistical analyses for this end point

    Secondary: Phase I - Number of subjects experiencing at least one Adverse Event (AE).

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    End point title
    		 Phase I - Number of subjects experiencing at least one Adverse Event (AE).
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 23 months after enrollment
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28 [3]
    Units: participants
        number (not applicable)
    28
    Notes
    [3] - Safety Set
    No statistical analyses for this end point

    Secondary: Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).

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    End point title
    		 Phase I - Number of Subjects Experiencing at Least One Serious Adverse Event (SAE).
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 23 months after enrollment
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28 [4]
    Units: participants
        number (not applicable)
    12
    Notes
    [4] - Safety Set
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Plasma concentration-time profiles

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    End point title
    		 Phase Ib/II - Plasma concentration-time profiles
    End point description
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to plasma concentration time profiles were not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed/ collected for this end point.
    End point type
    Secondary
    End point timeframe
    28-day cycles
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicabe
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Overall Response Rate (ORR)

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    End point title
    		 Phase Ib/II - Overall Response Rate (ORR)
    End point description
    ORR is defined as the proportion of patients with a best overall response of complete response or partial response. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed/ collected for this end point.
    End point type
    Secondary
    End point timeframe
    Approximately 23 months after enrollment
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Progression Free Survival (PFS)

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    End point title
    		 Phase Ib/II - Progression Free Survival (PFS)
    End point description
    PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    Approximately 23 months after enrollment
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Duration Of Response (DOR)

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    End point title
    		 Phase Ib/II - Duration Of Response (DOR)
    End point description
    DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer. Due to the halt of enrollment during the Phase Ib part of the study, this analysis was not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    Approximately 23 months after enrollment
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Pharmacokinetic Parameters: AUCtau

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    End point title
    		 Phase Ib/II - Pharmacokinetic Parameters: AUCtau
    End point description
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    28-day cycles
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Pharmacokinetic Parameters: Cmin

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    End point title
    		 Phase Ib/II - Pharmacokinetic Parameters: Cmin
    End point description
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    28-day cycles
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Pharmacokinetic Parameters: Cmax

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    End point title
    		 Phase Ib/II - Pharmacokinetic Parameters: Cmax
    End point description
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    28-day cycles
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Pharmacokinetic Parameters: Tmax

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    End point title
    		 Phase Ib/II - Pharmacokinetic Parameters: Tmax
    End point description
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    28-day cycles
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Secondary: Phase Ib/II - Pharmacokinetic Parameters: Racc

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    End point title
    		 Phase Ib/II - Pharmacokinetic Parameters: Racc
    End point description
    Due to the halt of enrollment during the Phase Ib part of the study, all analyses related to pharmacokinetic parameters were not performed. Subsequently, Phase II of the study did not enroll any subjects. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was analyzed for this end point.
    End point type
    Secondary
    End point timeframe
    28-day cycles
    End point values
    		 Phase I (Dose Escalation)
    Number of subjects analysed
    28
    Units: Not Applicable
        number (not applicable)
    999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected during the study, which began recruitment on 10-July-2013 and concluded on 13-April-2015.
    Adverse event reporting additional description
    An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been obtained.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    MedDRA
    Reporting groups
    Reporting group title
    Phase Ib: LEE011 200 mg + LGX818 300 mg (SS)
    Reporting group description
    		 Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment. Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment.

    Reporting group title
    Phase Ib: LEE011 300 mg + LGX818 200 mg (SS)
    Reporting group description
    		 Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment. Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment.

    Reporting group title
    Phase Ib: LEE011 400 mg + LGX818 100 mg (SS)
    Reporting group description
    		 Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment. Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment.

    Reporting group title
    Phase Ib: LEE011 400 mg + LGX818 200 mg (SS)
    Reporting group description
    		 Ribociclib (LEE011) was provided in capsule form for oral use and was to be taken orally, once a day for 21 consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment. Encorafenib (LGX818) was to be provided in capsule form for oral use and taken orally, once a day for 28 consecutive days as part of each 28-day cycle of treatment.

    Serious adverse events
    		 Phase Ib: LEE011 200 mg + LGX818 300 mg (SS) Phase Ib: LEE011 300 mg + LGX818 200 mg (SS) Phase Ib: LEE011 400 mg + LGX818 100 mg (SS) Phase Ib: LEE011 400 mg + LGX818 200 mg (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    5 / 12 (41.67%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    1
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Brain oedema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Syncope
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Memory impairment
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Simple partial seizures
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Systemic inflammatory response syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Transaminases increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chest wall abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phase Ib: LEE011 200 mg + LGX818 300 mg (SS) Phase Ib: LEE011 300 mg + LGX818 200 mg (SS) Phase Ib: LEE011 400 mg + LGX818 100 mg (SS) Phase Ib: LEE011 400 mg + LGX818 200 mg (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    11 / 12 (91.67%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin papilloma
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Acanthoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infected neoplasm
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neoplasm
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    2
    Embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    6 / 12 (50.00%)
    4 / 6 (66.67%)
    3 / 4 (75.00%)
         occurrences all number
    2
    6
    4
    3
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Chills
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Localised oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Xerosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Penile oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scrotal oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scrotal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scrotal swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Mood swings
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Anger
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mental status changes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    1
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    1
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood iron decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Troponin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post procedural complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post procedural discharge
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    0
    2
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    1
    Dysgeusia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Balance disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Partial seizures
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    2
    1
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    0
    2
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Increased tendency to bruise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Vision blurred
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blepharospasm
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dry eye
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye discharge
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Photophobia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    6 / 12 (50.00%)
    4 / 6 (66.67%)
    4 / 4 (100.00%)
         occurrences all number
    2
    6
    4
    4
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 12 (25.00%)
    3 / 6 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3
    3
    2
    Constipation
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    1
    2
    Stomatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cheilitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival discolouration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingival ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Glossitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Retching
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 6 (33.33%)
    7 / 12 (58.33%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    7
    3
    1
    Pruritus
         subjects affected / exposed
    2 / 6 (33.33%)
    7 / 12 (58.33%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    7
    1
    2
    Alopecia
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    1
    1
    Dry skin
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 12 (33.33%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Rash
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    0
    2
    Hyperkeratosis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    0
    2
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Palmoplantar keratoderma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Skin sensitisation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Transient acantholytic dermatosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Actinic keratosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cold sweat
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ephelides
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Intertrigo
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Leukoplakia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain of skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin hypopigmentation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vitiligo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cushingoid
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    4
    1
    0
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 12 (25.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Neck pain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    1
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Osteoporosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Periarthritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin candida
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dermatitis infected
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Fungal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Furuncle
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    3
    1
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Dehydration
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2013
    Protocol Amendment 1 primarily addressed changes to the protocol required as a result of Health Authority feedback. In addition, minor administrative changes to the protocol were also included.
    30 Sep 2013
    Protocol Amendment 2 introduced the following changes based on emerging safety data: • Additional time points were added to the ECG monitoring schedule to assess the safety and tolerability of ribociclib. • Hematological toxicity regimen was no longer pursued. All references to this alternate dosing regimen were removed from the protocol. Only the 21 consecutive days dosing followed by a 7-day planned break regimen was used in this study.
    20 Dec 2013
    Protocol Amendment 3 introduced new safety monitoring for visual toxicities, including routine ophthalmic examinations, in order to monitor for the potential risk of retinal/ocular changes and included recommendations for encorafenib dose modifications for visual toxicity. In addition, definitions of ophthalmologic DLTs were provided.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Aug 2014
    Study recruitment was halted on 07-Aug-2014 during the Phase Ib part of the study. The Phase II part of the study was not performed. Subsequently, no subjects were enrolled in the Phase II part of the study. Early termination of the study was not due to any safety concerns.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    N/A
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    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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