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    Clinical Trial Results:
    A phase Ib/II open-label, multi-center study of the combination of MEK162 plus AMG 479 (ganitumab) in adult patients with selected advanced solid tumors

    Summary
    EudraCT number
    		 2012-000305-76
    Trial protocol
    		 ES   GB   BE   FR   DE   IT  
    Global end of trial date
    01 Apr 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CMEK162X2111
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01562899
    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
    01 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of Phase Ib was to estimate the maximum tolerated dose (MTD(s)) and/or recommended Phase II dose (RP2D(s)) of binimetinib in combination with ganitumab in patients with advanced KRAS - or BRAF-mutant solid tumors. The primary objective of Phase II was to estimate the antitumor activity of the binimetinib and ganitumab combination in patients with KRAS-mutant colorectal cancer (CRC, arm 1), with pancreatic adenocarcinoma (arm 2), and in patients with BRAF-mutant melanoma (arm 3). The study was terminated early due to the current landscape for anti-melanoma therapies and the limited clinical activity observed with the study treatment.
    Protection of trial subjects
    The study was conducted according to the ethical principles of the Declaration of Helsinki. Eligible patients were only included in the study after providing written (witnessed, where required by law or regulation), IEC/IRB-approved informed consent or, if incapable of doing so, after such consent had been provided by a legally acceptable representative of the patient. In cases where the patient’s representative gave consent, the patient was to be informed about the study to the extent possible given his/her understanding.
    Background therapy
    		 Not Applicable.
    Evidence for comparator
    		 Not Applicable.
    Actual start date of recruitment
    27 Aug 2012
    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
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    77
    EEA total number of subjects
    53
    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)
    59
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment began on 27-Aug-2012 to the CMEK162X2111 trial. A total of 77 subjects were enrolled. The last subject's last visit occurred on 01-Apr-2015. Not completed subjects represent those subjects that stopped treatment early, due to a specific reason.

    Pre-assignment
    Screening details
    		 Based on the limited clinical activity of the binimetinib combination treatment and the changed landscape for anti-melanoma therapies, the sponsor decided to halt recruitment on 7-Jan-2014. This halt was not a consequence of any safety concerns, and the treatment of patients in the study continued according to the protocol.

    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
    Blinding implementation details are not applicable, as this was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort)
    Arm description
    		 30 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 30 mg / AMG 12 mg/kg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was supplied as tablets with a dosage strengths of 15 mg.

    Investigational medicinal product name
    Ganitumab
    Investigational medicinal product code
    AMG 479
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganitumab was supplied as a sterile liquid for intravenous infusion every second week. Until April 2013, a frozen formulation with a concentration of 30 mg/mL was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/mL was used.

    Arm title
    		 Phase Ib: MEK 45 mg + 9 mg/kg (Cohort)
    Arm description
    		 45 mg binimetinib bid + 9 mg/kg ganitumab q2w (MEK 45 mg / AMG 9 mg/kg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was supplied as tablets with a dosage strengths of 15 mg.

    Investigational medicinal product name
    Ganitumab
    Investigational medicinal product code
    AMG 479
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganitumab was supplied as a sterile liquid for intravenous infusion every second week. Until April 2013, a frozen formulation with a concentration of 30 mg/mL was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/mL was used.

    Arm title
    		 Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort)
    Arm description
    		 45 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 45 mg / AMG 12 mg/kg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was supplied as tablets with a dosage strengths of 15 mg.

    Investigational medicinal product name
    Ganitumab
    Investigational medicinal product code
    AMG 479
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganitumab was supplied as a sterile liquid for intravenous infusion every second week. Until April 2013, a frozen formulation with a concentration of 30 mg/mL was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/mL was used.

    Arm title
    		 Phase II: CRC (KRAS)
    Arm description
    		 Patients with KRAS mutant colorectal cancer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was supplied as tablets with a dosage strengths of 15 mg.

    Investigational medicinal product name
    Ganitumab
    Investigational medicinal product code
    AMG 479
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganitumab was supplied as a sterile liquid for intravenous infusion every second week. Until April 2013, a frozen formulation with a concentration of 30 mg/mL was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/mL was used.

    Arm title
    		 Phase II: Pancreatic
    Arm description
    		 Patients with metastatic pancreatic cancer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was supplied as tablets with a dosage strengths of 15 mg.

    Investigational medicinal product name
    Ganitumab
    Investigational medicinal product code
    AMG 479
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganitumab was supplied as a sterile liquid for intravenous infusion every second week. Until April 2013, a frozen formulation with a concentration of 30 mg/mL was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/mL was used.

    Arm title
    		 Phase II: Melanoma
    Arm description
    		 Patients with mutant BRAF V600 melanoma.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was supplied as tablets with a dosage strengths of 15 mg.

    Investigational medicinal product name
    Ganitumab
    Investigational medicinal product code
    AMG 479
    Other name
    Pharmaceutical forms
    Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ganitumab was supplied as a sterile liquid for intravenous infusion every second week. Until April 2013, a frozen formulation with a concentration of 30 mg/mL was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/mL was used.

    Number of subjects in period 1
    		Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort) Phase Ib: MEK 45 mg + 9 mg/kg (Cohort) Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort) Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma
    Started
    7
    6
    6
    26
    20
    12
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    7
    6
    6
    26
    20
    12
         Consent withdrawn by subject
    -
    1
    -
    -
    -
    1
         Adverse event, non-fatal
    3
    1
    2
    5
    5
    1
         Death
    -
    1
    -
    -
    -
    -
         Disease Progression
    4
    3
    4
    21
    15
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort)
    Reporting group description
    		 30 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 30 mg / AMG 12 mg/kg)

    Reporting group title
    Phase Ib: MEK 45 mg + 9 mg/kg (Cohort)
    Reporting group description
    		 45 mg binimetinib bid + 9 mg/kg ganitumab q2w (MEK 45 mg / AMG 9 mg/kg)

    Reporting group title
    Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort)
    Reporting group description
    		 45 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 45 mg / AMG 12 mg/kg)

    Reporting group title
    Phase II: CRC (KRAS)
    Reporting group description
    		 Patients with KRAS mutant colorectal cancer.

    Reporting group title
    Phase II: Pancreatic
    Reporting group description
    		 Patients with metastatic pancreatic cancer.

    Reporting group title
    Phase II: Melanoma
    Reporting group description
    		 Patients with mutant BRAF V600 melanoma.

    Reporting group values
    		 Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort) Phase Ib: MEK 45 mg + 9 mg/kg (Cohort) Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort) Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma Total
    Number of subjects
    		 7 6 6 26 20 12 77
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 5 5 4 19 14 12 59
        >=65 years
    		 2 1 2 7 6 0 18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ± 12.8 49.3 ± 17.41 57.3 ± 12.56 58.2 ± 10.53 56.7 ± 10.57 47.8 ± 11.34 -
    Gender categorical
    Units: Subjects
        Female
    		 2 3 4 14 9 5 37
        Male
    		 5 3 2 12 11 7 40
    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:
    		 1 0 2 7 6 6 22
        1:
    		 6 6 4 19 13 6 54
        Missing:
    		 0 0 0 0 1 0 1
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 172.3 ± 10.96 167.4 ± 7.59 166.7 ± 11.91 166.7 ± 10.53 169.6 ± 8.74 167.3 ± 7.4 -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 89.76 ± 15.458 63.1 ± 12.046 74.95 ± 12.674 74.17 ± 17.554 60.18 ± 9.058 73.5 ± 11.269 -

    End points

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    End points reporting groups
    Reporting group title
    Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort)
    Reporting group description
    		 30 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 30 mg / AMG 12 mg/kg)

    Reporting group title
    Phase Ib: MEK 45 mg + 9 mg/kg (Cohort)
    Reporting group description
    		 45 mg binimetinib bid + 9 mg/kg ganitumab q2w (MEK 45 mg / AMG 9 mg/kg)

    Reporting group title
    Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort)
    Reporting group description
    		 45 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 45 mg / AMG 12 mg/kg)

    Reporting group title
    Phase II: CRC (KRAS)
    Reporting group description
    		 Patients with KRAS mutant colorectal cancer.

    Reporting group title
    Phase II: Pancreatic
    Reporting group description
    		 Patients with metastatic pancreatic cancer.

    Reporting group title
    Phase II: Melanoma
    Reporting group description
    		 Patients with mutant BRAF V600 melanoma.

    Subject analysis set title
    Phase Ib/II: MEK 30 mg + AMG 12 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic analysis set includes all patients who had at least one blood sample providing evaluable PK data. Patients were analyzed as treated.

    Subject analysis set title
    Phase Ib/II: MEK 45 mg + 9 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic analysis set includes all patients who had at least one blood sample providing evaluable PK data. Patients were analyzed as treated.

    Subject analysis set title
    Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic analysis set includes all patients who had at least one blood sample providing evaluable PK data. Patients were analyzed as treated.

    Primary: Phase Ib: Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) by measuring incidence of Dose Limiting Toxicities (DLTs)

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    End point title
    		 Phase Ib: Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) by measuring incidence of Dose Limiting Toxicities (DLTs) [1] [2]
    End point description
    MTDs and/or RP2Ds of MEK162 in combination with AMG479 were estimated by measuring incidence of DLTs in Cycle 1.
    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: Statistical analysis not applicable.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis not applicable.
    End point values
    		 Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort) Phase Ib: MEK 45 mg + 9 mg/kg (Cohort) Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort)
    Number of subjects analysed
    7
    6
    6
    Units: DLTs
        arithmetic mean (standard deviation)
    0.117 ± 0.067
    0.127 ± 0.077
    0.159 ± 0.108
    No statistical analyses for this end point

    Primary: Phase II: Antitumor activity of MEK162 in combination with AMG 479 by evaluating Objective Response Rate (ORR) in colorectal carcinoma and melanoma and at week 10 in pancreatic carcinoma: Objective Response Rate (ORR)

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    End point title
    		 Phase II: Antitumor activity of MEK162 in combination with AMG 479 by evaluating Objective Response Rate (ORR) in colorectal carcinoma and melanoma and at week 10 in pancreatic carcinoma: Objective Response Rate (ORR) [3] [4]
    End point description
    Estimation of the antitumor activity of MEK162 in combination with AMG479 by evaluating Objective Response Rate (ORR) according to RECIST 1.1 in colorectal carcinoma and melanoma and by evaluating the Disease Control Rate (DCR) per RECIST 1.1 at week 10 in pancreatic carcinoma. Given the lack of responses in study arms 1 and 3, and the limited clinical anti-tumor activity observed in study arm 2, the Bayesian analysis of DCR at 10 weeks and ORR was not performed. A summary of the best overall response based on investigator radiology assessment by study arm is below.
    End point type
    Primary
    End point timeframe
    Week 10 (approximately 24 months)
    Notes
    [3] - 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: Statistical analysis not applicable.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Given the lack of responses in study arms 1 and 3, and the limited clinical anti-tumor activity observed in study arm 2, the Bayesian analysis of DCR at 10 weeks and ORR was not performed.
    End point values
    		 Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma
    Number of subjects analysed
    26
    20
    12
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 13.2)
    5 (0.1 to 24.9)
    0 (0 to 26.5)
    No statistical analyses for this end point

    Primary: Phase II: Antitumor activity of MEK162 in combination with AMG 479 by evaluating Disease Control Rate (DCR) in colorectal carcinoma and melanoma and at week 10 in pancreatic carcinoma: Observed Disease Control Rate (DCR)

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    End point title
    		 Phase II: Antitumor activity of MEK162 in combination with AMG 479 by evaluating Disease Control Rate (DCR) in colorectal carcinoma and melanoma and at week 10 in pancreatic carcinoma: Observed Disease Control Rate (DCR) [5] [6]
    End point description
    Estimation of the antitumor activity of MEK162 in combination with AMG479 by evaluating Objective Response Rate (ORR) according to RECIST 1.1 in colorectal carcinoma and melanoma and by evaluating the Disease Control Rate (DCR) per RECIST 1.1 at week 10 in pancreatic carcinoma. A summary of the observed BOR and ORR and 95% confidence intervals up to the time of cut-off is described below.
    End point type
    Primary
    End point timeframe
    Week 10 (approximately 24 months)
    Notes
    [5] - 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: Statistical analysis not applicable.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis not applicable.
    End point values
    		 Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma
    Number of subjects analysed
    26
    20
    12
    Units: percentage of subjects
        number (confidence interval 95%)
    38.5 (20.2 to 59.4)
    35 (15.4 to 59.2)
    0 (0 to 26.5)
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of single and multiple dose pharmacokinetics (PK) profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentrations and basic PK parameters of MEK162: Area Under the Curve 0-8 hrs (AUC-8hr)

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    End point title
    		 (Phase Ib/II) Determination of single and multiple dose pharmacokinetics (PK) profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentrations and basic PK parameters of MEK162: Area Under the Curve 0-8 hrs (AUC-8hr)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    60
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    933 ± 52.6
    1439.7 ± 33.1
    1576.8 ± 47.8
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Area Under the Curve 0-24 Hrs (AUC-24hr)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Area Under the Curve 0-24 Hrs (AUC-24hr)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    60
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1450.5 ± 28.4
    1923.4 ± 34.9
    2401.2 ± 46.7
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Area Under the Curve 0-inf (AUC0-inf)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Area Under the Curve 0-inf (AUC0-inf)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    4
    6
    42
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1692.9 ± 40.6
    1980 ± 34.9
    2536.7 ± 37.3
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Maximum Serum Concentration (Cmax)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Maximum Serum Concentration (Cmax)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    60
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    301.6 ± 90.6
    460.5 ± 56
    429.5 ± 59.2
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Time at which Cmax is Observed (Tmax)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Time at which Cmax is Observed (Tmax)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    60
    Units: hr
        geometric mean (geometric coefficient of variation)
    1.6 ± 75
    1.5 ± 76.7
    1.9 ± 90.6
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Half life (T1/2)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Half life (T1/2)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    4
    6
    45
    Units: hr
        geometric mean (geometric coefficient of variation)
    6.6 ± 25.4
    3.9 ± 43.3
    6.7 ± 50.2
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Area Under the Curve 0-8 Hrs (AUC-8hr)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Area Under the Curve 0-8 Hrs (AUC-8hr)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    3
    6
    32
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1428.6 ± 22.7
    1421.7 ± 26.9
    1745.6 ± 72.2
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Maximum Serum Concentration (Cmax)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Maximum Serum Concentration (Cmax)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 and are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    3
    6
    32
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    338.9 ± 10
    358.1 ± 43.7
    495.8 ± 79
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Time at which Cmax is observed (Tmax)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Time at which Cmax is observed (Tmax)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 and are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    3
    6
    32
    Units: hr
        geometric mean (geometric coefficient of variation)
    1 ± 79.1
    1.9 ± 46.8
    1.5 ± 77.8
    No statistical analyses for this end point

    Secondary: (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Accumulation Ratio (Racc)

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    End point title
    		 (Phase Ib/II) Determination of Single and Multiple Dose Pharmacokinetics (PK) Profile of MEK162 in Combination With AMG 479 (Ganitumab) by Measuring Time vs. Plasma Concentrations and Basic PK Parameters of MEK162: Accumulation Ratio (Racc)
    End point description
    Determination of single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different time points prior and post study drug combination dosing. Given that the enrollment to the study was prematurely stopped, PK results up to the data cut-off date 23-Sep-2014 are being reported. No additional PK data analysis was performed after this data cut-off.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 15)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    3
    6
    32
    Units: (hr*ng/mL) / (hr*ng/mL)
        geometric mean (geometric coefficient of variation)
    1.7 ± 27.7
    1 ± 28.6
    1.2 ± 53.9
    No statistical analyses for this end point

    Secondary: AMG 479 (ganitumab) Pharmacokinetic (PK) concentrations during the first cycle by dose cohort: Concentration at time point 0 (C0)

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    End point title
    		 AMG 479 (ganitumab) Pharmacokinetic (PK) concentrations during the first cycle by dose cohort: Concentration at time point 0 (C0)
    End point description
    The PK of AMG 479 (ganitumab) was assessed in this study by collecting the concentration at the end of infusion and the concentration 24 hours (CEOI) after the start of the infusion (C24) of AMG 479 (ganitumab) during Day 1 of Cycle 1.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    64
    Units: ug/mL
        median (full range (min-max))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 175)
    No statistical analyses for this end point

    Secondary: AMG 479 (Ganitumab) Pharmacokinetic (PK) Concentrations During the First Cycle by Dose Cohort: Concentration at the End Of the Infusion (CEOI)

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    End point title
    		 AMG 479 (Ganitumab) Pharmacokinetic (PK) Concentrations During the First Cycle by Dose Cohort: Concentration at the End Of the Infusion (CEOI)
    End point description
    The PK of AMG 479 (ganitumab) was assessed in this study by collecting the concentration at the end of infusion and the concentration 24 hours (CEOI) after the start of the infusion (C24) of AMG 479 (ganitumab) during Day 1 of Cycle 1.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    61
    Units: ug/mL
        median (full range (min-max))
    237 (176 to 341)
    125 (105 to 212)
    193 (0 to 382)
    No statistical analyses for this end point

    Secondary: AMG 479 (Ganitumab) Pharmacokinetic (PK) Concentrations During the First Cycle by Dose Cohort: Concentration 24 hours (C24)

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    End point title
    		 AMG 479 (Ganitumab) Pharmacokinetic (PK) Concentrations During the First Cycle by Dose Cohort: Concentration 24 hours (C24)
    End point description
    The PK of AMG 479 (ganitumab) was assessed in this study by collecting the concentration at the end of infusion and the concentration 24 hours (CEOI) after the start of the infusion (C24) of AMG 479 (ganitumab) during Day 1 of Cycle 1.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1)
    End point values
    		 Phase Ib/II: MEK 30 mg + AMG 12 mg/kg Phase Ib/II: MEK 45 mg + 9 mg/kg Phase Ib/II: MEK 45 mg + AMG 12 mg/kg
    Number of subjects analysed
    7
    6
    60
    Units: ug/mL
        median (full range (min-max))
    140 (95 to 191)
    77.7 (59 to 143)
    128 (0 to 271)
    No statistical analyses for this end point

    Secondary: Phase Ib: Preliminary anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating the Overall Response Rate (ORR), Duration of Response (DOR) and Progression Free Survival (PFS)

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    End point title
    		 Phase Ib: Preliminary anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating the Overall Response Rate (ORR), Duration of Response (DOR) and Progression Free Survival (PFS) [7]
    End point description
    The assessment the preliminary anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating Overall Response Rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS) as assessed by the investigator according to RECIST 1.1. No formal efficacy analyses of patients in Phase Ib of the study were performed. 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 (approximately 6 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis not applicable.
    End point values
    		 Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort) Phase Ib: MEK 45 mg + 9 mg/kg (Cohort) Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort)
    Number of subjects analysed
    7
    6
    6
    Units: Not Applicable
        number (not applicable)
    999
    999
    999
    No statistical analyses for this end point

    Secondary: Phase II: Further anti-tumor activity of MEK162 & AMG 479 (ganitumab) in combination by evaluating the DOR, PFS and OS by evaluating Disease Control Rate for colorectal carcinoma and melanoma: Progression-free Survival (PFS)

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    End point title
    		 Phase II: Further anti-tumor activity of MEK162 & AMG 479 (ganitumab) in combination by evaluating the DOR, PFS and OS by evaluating Disease Control Rate for colorectal carcinoma and melanoma: Progression-free Survival (PFS) [8]
    End point description
    To further assess the anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating the Duration of Response (DOR) and Progression Free Survival (PFS) per RECIST 1.1 and Overall Survival in all phase II patients and by evaluating the Disease Control Rate (DCR) per RECIST 1.1 for colorectal carcinoma and melanoma. Given the lack of responses in study arms 1 and 3, and the limited clinical anti-tumor activity observed in study arm 2, the Bayesian analysis of DCR at 10 weeks and ORR was not performed. Median time of Progression-free Survival (PFS) was estimated for the 3 arms of patients in Phase II.
    End point type
    Secondary
    End point timeframe
    Approximately 24 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Given the lack of responses in study arms 1 and 3, and the limited clinical anti-tumor activity observed in study arm 2, the Bayesian analysis of DCR at 10 weeks and ORR was not performed.
    End point values
    		 Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma
    Number of subjects analysed
    26
    20
    12
    Units: months
        number (confidence interval 95%)
    2.2 (1.4 to 2.4)
    1.5 (1.4 to 4)
    1.6 (1.5 to 2.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AE) were collected during the study, which began in August 2012 and concluded in 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
    17
    Reporting groups
    Reporting group title
    Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort)
    Reporting group description
    		 30 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 30 mg / AMG 12 mg/kg)

    Reporting group title
    Phase Ib: MEK 45 mg + 9 mg/kg (Cohort)
    Reporting group description
    		 45 mg binimetinib bid + 9 mg/kg ganitumab q2w (MEK 45 mg / AMG 9 mg/kg)

    Reporting group title
    Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort)
    Reporting group description
    		 45 mg binimetinib bid + 12 mg/kg ganitumab q2w (MEK 45 mg / AMG 12 mg/kg)

    Reporting group title
    Phase II: CRC (KRAS)
    Reporting group description
    		 Patients with KRAS mutant colorectal cancer.

    Reporting group title
    Phase II: Pancreatic
    Reporting group description
    		 Patients with metastatic pancreatic cancer.

    Reporting group title
    Phase II: Melanoma
    Reporting group description
    		 Patients with mutant BRAF V600 melanoma.

    Serious adverse events
    		 Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort) Phase Ib: MEK 45 mg + 9 mg/kg (Cohort) Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort) Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    13 / 26 (50.00%)
    14 / 20 (70.00%)
    3 / 12 (25.00%)
         number of deaths (all causes)
    0
    1
    0
    1
    5
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    General physical health deterioration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Pneumonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Blood bilirubin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Lipase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Troponin I increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Sinus bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Hemianopia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Convulsion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (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
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Colitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (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
    Colitis ischaemic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Haematemesis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Melaena
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 26 (11.54%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    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 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         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
    IIeus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         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
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (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
    Escherichia infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Biliary sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Biliary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Lung infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Urosepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (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
    Hyperglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phase Ib: MEK 30 mg + AMG 12 mg/kg (Cohort) Phase Ib: MEK 45 mg + 9 mg/kg (Cohort) Phase Ib: MEK 45 mg + AMG 12 mg/kg (Cohort) Phase II: CRC (KRAS) Phase II: Pancreatic Phase II: Melanoma
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    26 / 26 (100.00%)
    20 / 20 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    4 / 26 (15.38%)
    5 / 20 (25.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    0
    4
    5
    1
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Pallor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    7 / 26 (26.92%)
    6 / 20 (30.00%)
    2 / 12 (16.67%)
         occurrences all number
    3
    3
    2
    7
    6
    2
    Fatigue
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    6 / 26 (23.08%)
    14 / 20 (70.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    3
    6
    14
    1
    Asthenia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    5 / 26 (19.23%)
    1 / 20 (5.00%)
    4 / 12 (33.33%)
         occurrences all number
    2
    2
    1
    5
    1
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    7 / 26 (26.92%)
    7 / 20 (35.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    7
    7
    1
    Chills
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    5 / 26 (19.23%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    5
    2
    0
    Face oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Mucosal dryness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Axillary pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Generalised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Localised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Medical device complication
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Mucosal discolouration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Dyspareunia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    6 / 26 (23.08%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    6
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 26 (15.38%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    4
    1
    1
    Productive cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Pneumonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Laryngospasm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    1
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Nightmare
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    14 / 26 (53.85%)
    4 / 20 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    2
    14
    4
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    1
    1
    1
    Amylase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    3
    0
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    0
    1
    2
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    5 / 26 (19.23%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    5
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    7 / 26 (26.92%)
    5 / 20 (25.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    1
    7
    5
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 26 (11.54%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    3
    1
    0
    Blood calcium increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 26 (15.38%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    4
    3
    0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    4 / 20 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Troponin I increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood urine present
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Protein total decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Stoma site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Waist circumference increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    Wound
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Wound secretion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0
    2
    3
    0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Ageusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Migraine
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nerve compression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    9 / 26 (34.62%)
    8 / 20 (40.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    9
    8
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    9 / 26 (34.62%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    9
    2
    0
    Lymphopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    1
    0
    0
    1
    Retinal detachment
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    2
    0
    0
    1
    3
    Periorbital oedema
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Chorioretinopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 26 (15.38%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    4
    0
    0
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    1
    0
    3
    Eyelid oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Maculopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Retinal pigment epitheliopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    0
    0
    0
    2
    4
    Retinopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    3
    2
    0
    Subretinal fluid
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    4 / 20 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Visual impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Eye colour change
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Corneal thickening
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Lenticular opacities
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Metamorphopsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ocular hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Optic disc disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Retinal artery embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Retinal disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vitreous detachment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    13 / 26 (50.00%)
    7 / 20 (35.00%)
    2 / 12 (16.67%)
         occurrences all number
    3
    3
    4
    13
    7
    2
    Vomiting
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    11 / 26 (42.31%)
    11 / 20 (55.00%)
    2 / 12 (16.67%)
         occurrences all number
    4
    3
    2
    11
    11
    2
    Nausea
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    10 / 26 (38.46%)
    11 / 20 (55.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    3
    1
    10
    11
    1
    Stomatitis
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    5 / 26 (19.23%)
    7 / 20 (35.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    3
    2
    5
    7
    0
    Constipation
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    8 / 26 (30.77%)
    7 / 20 (35.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    1
    8
    7
    1
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    4 / 26 (15.38%)
    5 / 20 (25.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    4
    5
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    3
    2
    0
    Abdominal distension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Ascites
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    0
    2
    2
    2
    Dry mouth
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    6 / 20 (30.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    2
    6
    0
    Duodenal ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastric ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    3 / 20 (15.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Oesophagitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Chapped lips
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Glossitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rectal tenesmus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Retching
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tongue oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    4 / 26 (15.38%)
    4 / 20 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    3
    4
    4
    1
    Dermatitis acneiform
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    7 / 26 (26.92%)
    8 / 20 (40.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    3
    1
    7
    8
    1
    Rash maculo-papular
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    5 / 26 (19.23%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0
    5
    1
    0
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    10 / 26 (38.46%)
    4 / 20 (20.00%)
    5 / 12 (41.67%)
         occurrences all number
    0
    1
    2
    10
    4
    5
    Rash erythematous
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Skin fissures
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    Circumoral oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Erythema nodosum
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    2
    2
    0
    Skin toxicity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Acne
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin discolouration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Renal failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Calculus bladder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Myositis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    1
    2
    0
    Bacteraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Biliary sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Fungal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nail infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    7 / 26 (26.92%)
    8 / 20 (40.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    4
    7
    8
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 26 (7.69%)
    7 / 20 (35.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    1
    2
    7
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    2
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    2
    2
    0
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    5 / 26 (19.23%)
    4 / 20 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    5
    4
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
    5 / 20 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    5
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    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
    24 May 2012
    Protocol amendment 1 was issued before the start of enrollment to modify contraception requirements, to add clarifications on the dose-escalation procedures, and to revise DLT definitions. Furthermore, enhanced safety measures were implemented (more frequent monitoring of ocular events, measurements of liver transaminases, liver function tests and cardiac monitoring).
    23 Sep 2013
    Protocol amendment 2 was issued after the dose-escalation part was completed. In this amendment, the DLT criteria were updated according to the knowledge and the clinical experience with binimetinib at the time of the amendment, and the dose modification recommendations were adapted accordingly. The number of patients who experienced DLTs during the dose-escalation part was not affected.
    27 Jan 2014
    Protocol amendment 3 was issued following the enrollment halt. The protocol was amended to remove follow-up for progression and survival. Of note, there were no changes to the safety follow-up (including 30-day safety follow-up and follow-up for neutralizing antibodies).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Jan 2014
    Based on the limited clinical activity of the binimetinib combination treatment and the changed landscape for anti-melanoma therapies, Novartis decided to halt recruitment on 7-Jan-2014. The recruitment halt was not a consequence of any safety concerns, and the treatment of patients participating in the study continued according to the protocol.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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