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    Clinical Trial Results:
    A phase Ib/II, open-label, multicenter study of AEB071 and MEK162 in adult patients with metastatic uveal melanoma

    Summary
    EudraCT number
    		 2013-000281-11
    Trial protocol
    		 DE   NL   ES   GB   IT  
    Global end of trial date
    15 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    13 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CMEK162X2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01801358
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Array BioPharma, Inc.
    Sponsor organisation address
    3200 Walnut 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
    15 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase Ib To estimate the MTD and/or RP2D of sotrastaurin in combination with binimetinib in patients with metastatic uveal melanoma. Phase II To estimate and compare the antitumor activity of the sotrastaurin and binimetinib combination (Arm 1) and binimetinib alone (Arm 2) in patients with metastatic uveal melanoma.
    Protection of trial subjects
    The study was conducted according to the ethical principles of the Declaration of Helsinki. Informed consent was obtained from each patient in writing before starting any study-specific procedure. The study was described by the Investigator or delegate, who answered any questions, and written information was also provided.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    26 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 11
    Worldwide total number of subjects
    38
    EEA total number of subjects
    31
    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)
    27
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The CMEK162X2203 study began recruitment on 26-Aug-2013 and concluded on 15-May-2015. Due to an enrollment halt, the Phase II part of the study was not conducted. The sponsor decided to permanently stop recruitment for the study prior to MTD determination.

    Pre-assignment
    Screening details
    		 Participant Flow and Baseline Demographics data represents the Full Analysis Set (FAS), which includes all patients who received at least one full or partial dose of sotrastaurin or binimetinib. Not completed subjects represents subjects that stopped treatment early, due to the corresponding reason.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The CMEK162X2203 study was open-label, therefore blinding implementation details are not applicable.

    Arms
    Arm title
    		 Phase Ib (Dose Escalation)
    Arm description
    		 Combination of sotrastaurin and binimetinib administered orally bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotrastaurin
    Investigational medicinal product code
    AEB071
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Combination of sotrastaurin and binimetinib administered orally bid.

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Combination of sotrastaurin and binimetinib administered orally bid.

    Number of subjects in period 1
    		Phase Ib (Dose Escalation)
    Started
    38
    Completed
    0
    Not completed
    38
         Physician decision
    1
         Consent withdrawn by subject
    3
         Adverse event, non-fatal
    4
         Disease Progression
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 The overall study reporting group is comprised of the Phase Ib part of the study, due to an enrollment halt during the Phase Ib dose-escalation part prior to determination of the MTD as dose escalation of sotrastaurin beyond the starting dose was prevented due to sub-optimal tolerability of the combination of sotrastaurin and binimetinib.

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 38 38
    Age categorical
    Units: Subjects
        < 65 Years
    		 27 27
        ≥ 65 Years
    		 11 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.4 ( 11.39 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 24 24
    Predominant Race
    Units: Subjects
        Caucasian
    		 31 31
        Unknown
    		 7 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 6
        Russian
    		 1 1
        Unknown
    		 10 10
        Other
    		 21 21
    Baseline WHO 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:
    		 32 32
        1:
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Phase Ib: AEB071 150 mg bid + MEK162 45mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 150 mg bid + MEK162 45 mg bid

    Subject analysis set title
    Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 200 mg bid + MEK162 45 mg bid

    Subject analysis set title
    Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 300 mg bid + MEK162 30 mg bid

    Subject analysis set title
    Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 300 mg bid + MEK162 45 mg bid

    Subject analysis set title
    Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 350 mg bid + MEK162 30 mg bid

    Subject analysis set title
    Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 400 mg bid + MEK162 30 mg bid

    Subject analysis sets values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects
    6
    6
    6
    6
    6
    8
    Age categorical
    Units: Subjects
        < 65 Years
    5
    5
    5
    3
    4
    5
        ≥ 65 Years
    1
    1
    1
    3
    2
    3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.7 ( 15.21 )
    57 ( 10.43 )
    52.8 ( 10.82 )
    59.8 ( 9.11 )
    56.8 ( 10.87 )
    61.5 ( 10.65 )
    Gender categorical
    Units: Subjects
        Female
    3
    2
    3
    2
    2
    2
        Male
    3
    4
    3
    4
    4
    6
    Predominant Race
    Units: Subjects
        Caucasian
    4
    3
    5
    5
    6
    8
        Unknown
    2
    3
    1
    1
    0
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1
    1
    2
    1
    1
    0
        Russian
    1
    0
    0
    0
    0
    0
        Unknown
    2
    4
    2
    1
    1
    0
        Other
    2
    1
    2
    4
    4
    8
    Baseline WHO 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:
    3
    6
    5
    5
    5
    8
        1:
    3
    0
    1
    1
    1
    0

    End points

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    End points reporting groups
    Reporting group title
    Phase Ib (Dose Escalation)
    Reporting group description
    		 Combination of sotrastaurin and binimetinib administered orally bid.

    Subject analysis set title
    Phase Ib: AEB071 150 mg bid + MEK162 45mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 150 mg bid + MEK162 45 mg bid

    Subject analysis set title
    Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 200 mg bid + MEK162 45 mg bid

    Subject analysis set title
    Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 300 mg bid + MEK162 30 mg bid

    Subject analysis set title
    Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 300 mg bid + MEK162 45 mg bid

    Subject analysis set title
    Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 350 mg bid + MEK162 30 mg bid

    Subject analysis set title
    Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    AEB071 400 mg bid + MEK162 30 mg bid

    Primary: Phase Ib: Incidence of Dose Limiting Toxicities (DLT) During the First Cycle

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    End point title
    		 Phase Ib: Incidence of Dose Limiting Toxicities (DLT) During the First Cycle [1]
    End point description
    A DLT is defined as an adverse event or abnormal laboratory value as defined in the protocol that is assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with AEB071and MEK162.
    End point type
    Primary
    End point timeframe
    Cycle 1 (up to 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 Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [2]
    6 [3]
    5 [4]
    6 [5]
    6 [6]
    4 [7]
    Units: DLTs
        Anaemia
    0
    0
    0
    1
    0
    0
        Diarrhoea
    0
    0
    2
    1
    0
    0
        Vomiting
    0
    0
    0
    1
    1
    1
        Nausea
    0
    0
    0
    1
    0
    1
        Fatigue
    0
    0
    1
    1
    0
    0
        General Physical Health Deterioration
    0
    0
    1
    0
    0
    0
        Malaise
    0
    0
    0
    1
    0
    0
        Blood Creatinine Increased
    0
    0
    0
    0
    1
    0
        Ejection Fraction Decreased
    0
    0
    0
    0
    0
    1
        Dermatitis Acneiform
    0
    2
    0
    0
    0
    0
        Rash
    0
    0
    0
    1
    0
    0
    Notes
    [2] - Dose Determining Set
    [3] - Dose Determining Set
    [4] - Dose Determining Set
    [5] - Dose Determining Set
    [6] - Dose Determining Set
    [7] - Dose Determining Set
    No statistical analyses for this end point

    Secondary: Phase Ib/II: The Number of Subjects Experiencing At Least One Adverse Event (AE)

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    End point title
    		 Phase Ib/II: The Number of Subjects Experiencing At Least One Adverse Event (AE)
    End point description
    An adverse event 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. Due to an enrollment halt, the Phase II part of the study was not conducted. 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
    From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [8]
    6 [9]
    6 [10]
    6 [11]
    6 [12]
    8 [13]
    Units: participants
    6
    6
    6
    6
    6
    8
    Notes
    [8] - Safety Set
    [9] - Safety Set
    [10] - Safety Set
    [11] - Safety Set
    [12] - Safety Set
    [13] - Safety Set
    No statistical analyses for this end point

    Secondary: Phase Ib/II: The Number of Subjects Experiencing At Least One Serious Adverse Event (SAE)

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    End point title
    		 Phase Ib/II: The Number of Subjects Experiencing At Least One Serious Adverse Event (SAE)
    End point description
    Serious adverse event (SAE) is defined as one of the following: • Is fatal or life-threatening • Results in persistent or significant disability/incapacity • Constitutes a congenital anomaly/birth defect • Is medically significant • Requires inpatient hospitalization or prolongation of existing hospitalization • Note that hospitalizations for the following reasons should not be reported as serious adverse events: - Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition - Elective or pre-planned treatment for a pre-existing condition that is unrelated to metastatic uveal melanoma and has not worsened since signing the informed consent • Social reasons and respite care in the absence of any deterioration in the patient’s general condition Due to an enrollment halt, the Phase II part of the study was not conducted. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value".
    End point type
    Secondary
    End point timeframe
    From first dose of Cycle 1, Day 1 (C1D1) to time to progression (up to 18 months from Last Patient First Visit)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [14]
    6 [15]
    6 [16]
    6 [17]
    6 [18]
    8 [19]
    Units: participants
    3
    1
    3
    4
    2
    6
    Notes
    [14] - Safety Set
    [15] - Safety Set
    [16] - Safety Set
    [17] - Safety Set
    [18] - Safety Set
    [19] - Safety Set
    No statistical analyses for this end point

    Secondary: Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Best Overall Response (BOR)

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    End point title
    		 Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Best Overall Response (BOR)
    End point description
    Assessment of the preliminary anti-tumor activity of AEB071 and MEK162 in combination. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (up to 28 days)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [20]
    6 [21]
    6 [22]
    6 [23]
    6 [24]
    8 [25]
    Units: participants
        Complete Response
    0
    0
    0
    0
    0
    0
        Partial Response
    0
    0
    0
    0
    0
    0
        Stable Disease
    5
    4
    4
    2
    3
    5
        Progressive disease
    1
    2
    1
    2
    3
    2
        Unknown
    0
    0
    1
    2
    0
    1
    Notes
    [20] - Full Analysis Set
    [21] - Full Analysis Set
    [22] - Full Analysis Set
    [23] - Full Analysis Set
    [24] - Full Analysis Set
    [25] - Full Analysis Set
    No statistical analyses for this end point

    Secondary: Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Duration of Response (DOR)

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    End point title
    		 Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Duration of Response (DOR)
    End point description
    Assessment of the preliminary anti-tumor activity of AEB071 and MEK162 in combination. Duration of Response (DOR) is not reported, since there were no responses of Complete Response (CR) or Partial Response (PR) at any time during the study. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was collected for this end point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (up to 28 days)
    End point values
    		 Phase Ib (Dose Escalation)
    Number of subjects analysed
    38 [26]
    Units: participants
    999
    Notes
    [26] - Full Analysis Set
    No statistical analyses for this end point

    Secondary: Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Progression Free Survival (PFS)

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    End point title
    		 Phase Ib: Assessment of The Preliminary Anti-tumor Activity - Progression Free Survival (PFS)
    End point description
    Assessment of the preliminary anti-tumor activity of AEB071 and MEK162 in combination. 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.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (up to 28 days)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [27]
    6 [28]
    6 [29]
    6 [30]
    6 [31]
    8 [32]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    3.6 (3.2 to 3.7)
    3.4 (1.6 to 3.7)
    4 (1.7 to 6.5)
    3.7 (1.2 to 5.3)
    3.1 (1.8 to 5.4)
    3.8 (1.9 to 11.5)
    Notes
    [27] - Full Analysis Set
    [28] - Full Analysis Set
    [29] - Full Analysis Set
    [30] - Full Analysis Set
    [31] - Full Analysis Set
    [32] - Full Analysis Set
    No statistical analyses for this end point

    Secondary: Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 1)

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    End point title
    		 Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [33]
    5 [34]
    6 [35]
    6 [36]
    4 [37]
    8 [38]
    Units: hr*ng/ml
        geometric mean (geometric coefficient of variation)
    7448.5 ( 46.34 )
    7136 ( 25.09 )
    15090 ( 53.89 )
    14051.2 ( 45.83 )
    18840.8 ( 36.24 )
    15217.1 ( 71.48 )
    Notes
    [33] - Pharmacokinetic Analysis Set
    [34] - Pharmacokinetic Analysis Set
    [35] - Pharmacokinetic Analysis Set
    [36] - Pharmacokinetic Analysis Set
    [37] - Pharmacokinetic Analysis Set
    [38] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 1)

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    End point title
    		 Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [39]
    5 [40]
    6 [41]
    6 [42]
    4 [43]
    8 [44]
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    1837.5 ( 35.9 )
    1932.5 ( 31.18 )
    2968.1 ( 58.32 )
    2813 ( 36.83 )
    4459 ( 26.45 )
    3768.7 ( 57.12 )
    Notes
    [39] - Pharmacokinetic Analysis Set
    [40] - Pharmacokinetic Analysis Set
    [41] - Pharmacokinetic Analysis Set
    [42] - Pharmacokinetic Analysis Set
    [43] - Pharmacokinetic Analysis Set
    [44] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 1)

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    End point title
    		 Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [45]
    5 [46]
    6 [47]
    6 [48]
    4 [49]
    8 [50]
    Units: hr
        median (full range (min-max))
    1.6 (0.4 to 4)
    1.1 (1 to 4)
    1.5 (0.5 to 2)
    1 (0.5 to 1.9)
    1 (1 to 2)
    2.1 (0.5 to 5.8)
    Notes
    [45] - Pharmacokinetic Analysis Set
    [46] - Pharmacokinetic Analysis Set
    [47] - Pharmacokinetic Analysis Set
    [48] - Pharmacokinetic Analysis Set
    [49] - Pharmacokinetic Analysis Set
    [50] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 15)

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    End point title
    		 Phase Ib: PK Parameters for AEB071 - AUC0-8hr (Cycle 1; Day 15)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [51]
    4 [52]
    2 [53]
    5 [54]
    5 [55]
    5 [56]
    Units: hr*ng/ml
        geometric mean (geometric coefficient of variation)
    5879.9 ( 32.46 )
    6330.3 ( 29.28 )
    16737.1 ( 17.56 )
    15313.6 ( 105.21 )
    15055.5 ( 78.89 )
    20629.7 ( 11.81 )
    Notes
    [51] - Pharmacokinetic Analysis Set
    [52] - Pharmacokinetic Analysis Set
    [53] - Pharmacokinetic Analysis Set
    [54] - Pharmacokinetic Analysis Set
    [55] - Pharmacokinetic Analysis Set
    [56] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 15)

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    End point title
    		 Phase lb: PK Parameters for AEB071 - Cmax (Cycle 1; Day 15)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [57]
    4 [58]
    2 [59]
    5 [60]
    5 [61]
    5 [62]
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    1244.6 ( 27.5 )
    1347.1 ( 28.56 )
    3065.6 ( 60.1 )
    3263.8 ( 96.11 )
    3597.2 ( 62.84 )
    3716.5 ( 23.72 )
    Notes
    [57] - Pharmacokinetic Analysis Set
    [58] - Pharmacokinetic Analysis Set
    [59] - Pharmacokinetic Analysis Set
    [60] - Pharmacokinetic Analysis Set
    [61] - Pharmacokinetic Analysis Set
    [62] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 15)

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    End point title
    		 Phase lb: PK Parameters for AEB071 - Tmax (Cycle 1; Day 15)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [63]
    4 [64]
    2 [65]
    5 [66]
    5 [67]
    5 [68]
    Units: hr
        median (full range (min-max))
    2 (1.1 to 8.3)
    1.5 (0.5 to 2)
    2.6 (1 to 4.2)
    3.9 (2 to 4.2)
    1.9 (0.5 to 2.1)
    2.1 (2 to 8)
    Notes
    [63] - Pharmacokinetic Analysis Set
    [64] - Pharmacokinetic Analysis Set
    [65] - Pharmacokinetic Analysis Set
    [66] - Pharmacokinetic Analysis Set
    [67] - Pharmacokinetic Analysis Set
    [68] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 1)

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    End point title
    		 Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [69]
    5 [70]
    6 [71]
    6 [72]
    5 [73]
    8 [74]
    Units: hr*ng/ml
        geometric mean (geometric coefficient of variation)
    1587.7 ( 55.75 )
    1496.7 ( 30.02 )
    1088.7 ( 49.45 )
    1590.5 ( 43.49 )
    984.4 ( 72.57 )
    962 ( 50.15 )
    Notes
    [69] - Pharmacokinetic Analysis Set
    [70] - Pharmacokinetic Analysis Set
    [71] - Pharmacokinetic Analysis Set
    [72] - Pharmacokinetic Analysis Set
    [73] - Pharmacokinetic Analysis Set
    [74] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 1)

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    End point title
    		 Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [75]
    5 [76]
    6 [77]
    6 [78]
    5 [79]
    8 [80]
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    362 ( 46.74 )
    432.6 ( 56.3 )
    245.4 ( 63.08 )
    328.4 ( 59.07 )
    243.5 ( 53.27 )
    222.8 ( 58.13 )
    Notes
    [75] - Pharmacokinetic Analysis Set
    [76] - Pharmacokinetic Analysis Set
    [77] - Pharmacokinetic Analysis Set
    [78] - Pharmacokinetic Analysis Set
    [79] - Pharmacokinetic Analysis Set
    [80] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 1)

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    End point title
    		 Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [81]
    5 [82]
    6 [83]
    6 [84]
    5 [85]
    8 [86]
    Units: hr
        median (full range (min-max))
    1.1 (1 to 3.8)
    1.1 (1 to 4.1)
    2 (1 to 2.1)
    4 (0.5 to 4.1)
    2 (0.6 to 2.3)
    1.1 (0.5 to 4)
    Notes
    [81] - Pharmacokinetic Analysis Set
    [82] - Pharmacokinetic Analysis Set
    [83] - Pharmacokinetic Analysis Set
    [84] - Pharmacokinetic Analysis Set
    [85] - Pharmacokinetic Analysis Set
    [86] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 15)

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    End point title
    		 Phase Ib: PK Parameters for MEK162 - AUC0-8hr (Cycle 1; Day 15)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [87]
    4 [88]
    4 [89]
    4 [90]
    5 [91]
    4 [92]
    Units: hr*ng/ml
        geometric mean (geometric coefficient of variation)
    1807.4 ( 43.6 )
    1927.9 ( 42.48 )
    1374.2 ( 68.21 )
    1454.7 ( 41.13 )
    1268.5 ( 70.41 )
    1275.8 ( 39.04 )
    Notes
    [87] - Pharmacokinetic Analysis Set
    [88] - Pharmacokinetic Analysis Set
    [89] - Pharmacokinetic Analysis Set
    [90] - Pharmacokinetic Analysis Set
    [91] - Pharmacokinetic Analysis Set
    [92] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 15)

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    End point title
    		 Phase lb: PK Parameters for MEK162 - Cmax (Cycle 1; Day 15)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [93]
    4 [94]
    4
    4 [95]
    5 [96]
    4 [97]
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    454.5 ( 42.42 )
    418.9 ( 34.62 )
    307 ( 88.45 )
    362.7 ( 59.8 )
    340.7 ( 80.64 )
    284.1 ( 52.79 )
    Notes
    [93] - Pharmacokinetic Analysis Set
    [94] - Pharmacokinetic Analysis Set
    [95] - Pharmacokinetic Analysis Set
    [96] - Pharmacokinetic Analysis Set
    [97] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Secondary: Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 15)

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    End point title
    		 Phase lb: PK Parameters for MEK162 - Tmax (Cycle 1; Day 15)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib: AEB071 150 mg bid + MEK162 45mg bid Phase Ib: AEB071 200 mg bid + MEK162 45 mg bid Phase Ib: AEB071 300 mg bid + MEK162 30 mg bid Phase Ib: AEB071 300 mg bid + MEK162 45 mg bid Phase Ib: AEB071 350 mg bid + MEK162 30 mg bid Phase Ib: AEB071 400 mg bid + MEK162 30 mg bid
    Number of subjects analysed
    6 [98]
    4 [99]
    4 [100]
    4 [101]
    5 [102]
    4 [103]
    Units: hr
        median (full range (min-max))
    2 (1.1 to 8.3)
    1.6 (1.1 to 4)
    3 (1 to 8.2)
    2.9 (2 to 4.1)
    1.9 (0.5 to 2.1)
    1.5 (0.5 to 8)
    Notes
    [98] - Pharmacokinetic Analysis Set
    [99] - Pharmacokinetic Analysis Set
    [100] - Pharmacokinetic Analysis Set
    [101] - Pharmacokinetic Analysis Set
    [102] - Pharmacokinetic Analysis Set
    [103] - Pharmacokinetic Analysis Set
    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 throughout the duration of the trial, which began in August, 2013 and concluded in May, 2015.
    Adverse event reporting additional description
    AE reporting is comprised of the Safety Set (SS), which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Phase Ib: AEB071 150 mg bid + MEK162 45 mg bid
    Reporting group description
    		 Analysis group comprised of the Safety Set, which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.

    Reporting group title
    Phase lb: AEB071 200 mg bid + MEK162 45 mg bid
    Reporting group description
    		 Analysis group comprised of the Safety Set, which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.

    Reporting group title
    Phase lb: AEB071 300 mg bid + MEK162 30 mg bid
    Reporting group description
    		 Analysis group comprised of the Safety Set, which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.

    Reporting group title
    Phase lb: AEB071 300 mg bid + MEK162 45 mg bid
    Reporting group description
    		 Analysis group comprised of the Safety Set, which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.

    Reporting group title
    Phase lb: AEB071 350 mg bid + MEK162 30 mg bid
    Reporting group description
    		 Analysis group comprised of the Safety Set, which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.

    Reporting group title
    Phase lb: AEB071 400 mg bid + MEK162 30 mg bid
    Reporting group description
    		 Analysis group comprised of the Safety Set, which is all patients who received at least one dose of AEB071 and MEK162, and have at least one valid post-baseline safety assessment.

    Serious adverse events
    		 Phase Ib: AEB071 150 mg bid + MEK162 45 mg bid Phase lb: AEB071 200 mg bid + MEK162 45 mg bid Phase lb: AEB071 300 mg bid + MEK162 30 mg bid Phase lb: AEB071 300 mg bid + MEK162 45 mg bid Phase lb: AEB071 350 mg bid + MEK162 30 mg bid Phase lb: AEB071 400 mg bid + MEK162 30 mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    6 / 8 (75.00%)
         number of deaths (all causes)
    4
    1
    1
    3
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    SINUS TACHYCARDIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    4 / 8 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL VARICES HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 3
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    ACUTE HEPATIC FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATOMEGALY
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ESCHERICHIA BACTERAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase Ib: AEB071 150 mg bid + MEK162 45 mg bid Phase lb: AEB071 200 mg bid + MEK162 45 mg bid Phase lb: AEB071 300 mg bid + MEK162 30 mg bid Phase lb: AEB071 300 mg bid + MEK162 45 mg bid Phase lb: AEB071 350 mg bid + MEK162 30 mg bid Phase lb: AEB071 400 mg bid + MEK162 30 mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    8 / 8 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR PAIN
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    0
    1
    0
    0
    3
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    5 / 8 (62.50%)
         occurrences all number
    3
    3
    4
    3
    3
    5
    OEDEMA PERIPHERAL
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    3 / 8 (37.50%)
         occurrences all number
    2
    2
    4
    3
    2
    3
    ASTHENIA
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    3
    2
    2
    2
    0
    3
    PYREXIA
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    MALAISE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    CHILLS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    3
    0
    1
    2
    0
    1
    COUGH
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    4 / 6 (66.67%)
    5 / 6 (83.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 8 (25.00%)
         occurrences all number
    4
    5
    1
    2
    3
    2
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    4
    1
    3
    3
    0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    2
    3
    1
    2
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    0
    1
    0
    0
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    1
    2
    2
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    WEIGHT INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Nervous system disorders
    DYSGEUSIA
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    1
    2
    2
    0
    CEREBROVASCULAR DISORDER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    PRESYNCOPE
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    3
    3
    0
    1
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Eye disorders
    CHORIORETINOPATHY
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    5 / 8 (62.50%)
         occurrences all number
    1
    1
    0
    0
    1
    5
    RETINAL DETACHMENT
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    3
    1
    1
    0
    0
    VISION BLURRED
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
         occurrences all number
    0
    2
    0
    2
    1
    2
    VISUAL IMPAIRMENT
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    1
    1
    0
    0
    3
    CATARACT
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    EYE DISORDER
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    EYELID OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    MACULAR OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    PERIORBITAL OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    RETINAL OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    RETINOPATHY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    6 / 6 (100.00%)
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    8 / 8 (100.00%)
         occurrences all number
    6
    5
    6
    6
    6
    8
    NAUSEA
         subjects affected / exposed
    6 / 6 (100.00%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    6 / 6 (100.00%)
    4 / 6 (66.67%)
    7 / 8 (87.50%)
         occurrences all number
    6
    3
    4
    6
    4
    7
    VOMITING
         subjects affected / exposed
    5 / 6 (83.33%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    5 / 6 (83.33%)
    5 / 6 (83.33%)
    7 / 8 (87.50%)
         occurrences all number
    5
    3
    5
    5
    5
    7
    CONSTIPATION
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 8 (50.00%)
         occurrences all number
    2
    2
    1
    0
    1
    4
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    STOMATITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    0
    2
    0
    DYSPEPSIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    FLATULENCE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    0
    1
    1
    DRY MOUTH
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    GASTRITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    IMPAIRED GASTRIC EMPTYING
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Hepatobiliary disorders
    HEPATIC PAIN
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    5 / 6 (83.33%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    1 / 8 (12.50%)
         occurrences all number
    5
    2
    2
    3
    2
    1
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    3
    3
    2
    0
    PRURITUS
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    2
    1
    0
    1
    DRY SKIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    ACNE
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    RASH MACULO-PAPULAR
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    ALOPECIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    PAIN OF SKIN
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    ERYTHEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    HYPERHIDROSIS
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    RASH FOLLICULAR
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    XERODERMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Renal and urinary disorders
    CHROMATURIA
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    2
    0
    0
    1
    RENAL COLIC
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    MYALGIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    BACK PAIN
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Infections and infestations
    RASH PUSTULAR
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 6 (66.67%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    4
    2
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
         occurrences all number
    1
    2
    1
    2
    1
    3
    DEHYDRATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    HYPOALBUMINAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    CACHEXIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2013
    Protocol Amendment 1 introduced the following changes: - In order to further reduce the risk of excess toxicity of this novel combination, the starting dose of binimetinib was reduced to 30 mg bid, 50% of the single-agent MTD. The provisional dose levels were adjusted accordingly. - Due to uncertainties regarding the potential AEs associated with this novel combination, DLT criteria for elevations in total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase, creatine kinase and worsening peripheral edema were modified, and eligibility criteria were modified to exclude patients with a serum creatinine > 1.5 x ULN. - Sotrastaurin is primarily metabolized by CYP3A4/5; therefore, the eligibility criteria were modified to exclude patients using medications and herbal supplements known to be strong inhibitors or inducers of CYP3A4/5.
    27 Nov 2013
    Protocol Amendment 2 introduced the following changes: - In phase II, to allow comparison of the preliminary anti-tumor activity of the combination of sotrastaurin and binimetinib with single-agent binimetinib. - To change the primary endpoint of the phase II part of the study from ORR to PFS. - To implement a Novartis Steering Committee to review the results of the formal interim analysis for futility in Phase II and define the scope of decisions that were to be made based on the results. - To clarify and update the inclusion and exclusion criteria: - Revised exclusion criterion #1 regarding active central nervous system lesions to align with binimetinib program standards. - Revised exclusion criterion #4 regarding history or current evident of retinal vein occlusion (RVO) or risk factors for RVO to align with binimetinib program standards. - Removed inclusion criterion regarding history of retinal degenerative disease. - Clarified exclusion criteria pertaining to prior exposure to a MEK inhibitor or a PKC inhibitor regarding patients who fail treatment in Phase Ib. - Revised exclusion criteria to extend period for contraception during dosing and after treatment discontinuation to 30 days to align with binimetinib program standards; also revised requirements for use of oral contraceptives to include use of a barrier method. - To introduce new and modify existing safety monitoring. - To include a blood sample request at baseline (Cycle 1, Day 1) and disease progression for assessment of circulating tumor DNA.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 May 2015
    Due to halted enrollment, the Phase II part of the study was not conducted. The Sponsor decided to permanently stop recruitment for the study prior to MTD determination. Remaining patients on treatment with binimetinib and sotrastaurin who were considered by the Investigator to be benefiting from their treatment could have continued treatment and were to be followed up as per protocol. No patients were ongoing as of the data cut-off date. After the last patient last visit (LPLV) was declared, the study was terminated.
    -

    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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