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    Clinical Trial Results:
    An Open-Label, 2-Cohort, Multicenter, Phase 2 Study of E7080 in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

    Summary
    EudraCT number
    		 2010-019526-14
    Trial protocol
    		 GB   DE  
    Global end of trial date
    05 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2016
    First version publication date
    30 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-G000-206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01136967
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake, United States, 07677
    Public contact
    Eisai Call Center, Eisai Inc., 888 422-4743, lmedinfo@eisai.net
    Scientific contact
    Eisai Call Center, Eisai Inc., 888 422-4743, lmedinfo@eisai.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Apr 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were: • To assess the objective response rate (ORR) (complete response + partial response [CR + PR]) of lenvatinib in subjects with unresectable Stage III or Stage IV melanoma not harboring the V600E BRAF mutation and disease progression following up to 2 prior systemic anticancer regiments for unresectable Stage III or Stage IV melanoma (Cohort 1). • To assess the ORR of lenvatinib in subjects with unresectable Stage III or Stage IV melanoma harboring the activating BRAF mutations (mainly the V600E mutation) and disease progression following BRAF V600E-targeted therapy (Cohort 2).
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    United States: 116
    Country: Number of subjects enrolled
    Australia: 30
    Worldwide total number of subjects
    182
    EEA total number of subjects
    36
    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)
    115
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at a total of 40 sites in Australia, Germany, United Kingdom, and United States.

    Pre-assignment
    Screening details
    		 A total of 298 participants were screened. Of these, 116 were screen failures and 182 received treatment (93 participants in Cohort 1 and 89 participants in Cohort 2). Out of the 116 screen failures, 97 participants fail to meet the inclusion/exclusion criteria, 11 withdrew consent, and 8 were excluded for other reasons.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (V600E BRAF negative)
    Arm description
    		 Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens excluding anti-vascular endothelial growth factor (anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Lenvima
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    24 mg lenvatinib, once daily (two 10-mg capsules and one 4-mg capsule) was administered at approximately the same time in the morning without regard to food intake for 28 days from Cycle 1 onward. If a dose was missed, it was to be taken within the 12 hours following the usual time of the morning dose. If more than 12 hours had elapsed from the time of the usual daily dose, lenvatinib was to be taken the next day at the usual time in the morning. If in the event a participant vomited after study drug administration, they were not to take another dose until the next scheduled dose.

    Arm title
    		 Cohort 2 (V600E BRAF positive)
    Arm description
    		 Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles. In addition to BRAF V600E-targeted therapy, participants may have received up to 2 prior systemic anticancer regimens (including immunotherapies but excluding anti-vascular endothelial growth factor (anti-VEGF) therapies) for unresectable Stage III or Stage IV disease.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    Lenvima, E7080
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    24 mg lenvatinib, once daily (two 10-mg capsules and one 4-mg capsule) was administered at approximately the same time in the morning without regard to food intake for 28 days from Cycle 1 onward. If a dose was missed, it was to be taken within the 12 hours following the usual time of the morning dose. If more than 12 hours had elapsed from the time of the usual daily dose, lenvatinib was to be taken the next day at the usual time in the morning. If in the event a participant vomited after study drug administration, they were not to take another dose until the next scheduled dose.

    Number of subjects in period 1
    		Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Started
    93
    89
    Completed
    69
    62
    Not completed
    24
    27
         Clinical progression
    3
    5
         Participant choice
    8
    3
         Consent withdrawn by subject
    1
    2
         Increase in lesion size
    -
    2
         Radiation
    1
    -
         Adverse event, non-fatal
    9
    12
         Non-compliance
    1
    -
         Diagnosis of second primary cancer
    -
    1
         Investigator's choice
    1
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (V600E BRAF negative)
    Reporting group description
    		 Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens excluding anti-vascular endothelial growth factor (anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.

    Reporting group title
    Cohort 2 (V600E BRAF positive)
    Reporting group description
    		 Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles. In addition to BRAF V600E-targeted therapy, participants may have received up to 2 prior systemic anticancer regimens (including immunotherapies but excluding anti-vascular endothelial growth factor (anti-VEGF) therapies) for unresectable Stage III or Stage IV disease.

    Reporting group values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive) Total
    Number of subjects
    		 93 89 182
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 62.5 ± 11.71 55 ± 14.18 -
    Gender categorical
    Units: Subjects
        Female
    		 29 39 68
        Male
    		 64 50 114
    AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry
    Units: Subjects
        Unresectable Stage III
    		 5 7 12
        Unresectable Stage IV
    		 88 82 170

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (V600E BRAF negative)
    Reporting group description
    		 Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens excluding anti-vascular endothelial growth factor (anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.

    Reporting group title
    Cohort 2 (V600E BRAF positive)
    Reporting group description
    		 Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles. In addition to BRAF V600E-targeted therapy, participants may have received up to 2 prior systemic anticancer regimens (including immunotherapies but excluding anti-vascular endothelial growth factor (anti-VEGF) therapies) for unresectable Stage III or Stage IV disease.

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 millimeters. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The Full Analysis Set (Intent-to-Treat [ITT] Analysis Set) included all participants who received at least 1 dose lenvatinib.
    End point type
    Primary
    End point timeframe
    From date of first dose of study drug until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 by the date of data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively)
    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: For each cohort, the null hypothesis that ORR is ≤10% was tested against the alternative hypothesis of an ORR ≥20%, using the 1-sample exact test of a single proportion, at the 1-sided 0.05 level. ORR is shown with corresponding 2-sided, exact binomial 95% confidence interval. Statistical results are found in the table for ORR with 95% CI.
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: Percentage of participants
        number (confidence interval 95%)
    8.6 (3.8 to 16.2)
    9 (4 to 16.9)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below. The Full Analysis Set (ITT Analysis Set) was used and included all participants who received at least 1 dose lenvatinib.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 2.9 years
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: Months
    median (confidence interval 95%)
        Determined by IRR
    3.7 (2.5 to 4.2)
    1.8 (1.8 to 2.2)
        Determined by Investigator
    3.7 (3.6 to 4.2)
    2.3 (1.9 to 3.4)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below. The Full Analysis Set (ITT Analysis Set) was used and included all participants who received at least 1 dose lenvatinib.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug until date of death from any cause or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 2.9 years
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: Months
        median (confidence interval 95%)
    8.9 (8.3 to 99999)
    6.3 (5.2 to 8.8)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD). To be assigned a BOR of SD, the time from the first administration of study drug until the date of documented SD needed to be greater than or equal to seven weeks based on IRR and Investigator's assessment. The Full Analysis Set (ITT Analysis Set) was used and included all participants who received at least 1 dose lenvatinib.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 2.9 years
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: Percentage of participants
    number (confidence interval 95%)
        Determined by IRR
    52.7 (42.1 to 63.1)
    34.8 (25 to 45.7)
        Determined by Investigator
    64.5 (53.9 to 74.2)
    48.3 (37.6 to 59.2)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (SD lasting greater than or equal to 23 weeks) based on IRR and Investigator's assessment. The Full Analysis Set (ITT Analysis Set) was used and included all participants who received at least 1 dose lenvatinib.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 2.9 years
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: Percentage of participants
    number (confidence interval 95%)
        Determined by IRR
    31.2 (22 to 41.6)
    14.6 (8 to 23.7)
        Determined by Investigator
    33.3 (23.9 to 43.9)
    20.2 (12.4 to 30.1)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib

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    End point title
    		 Number of Participants with Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
    End point description
    Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram. The Safety Analysis set was used and included all participants who received at least 1 dose of lenvatinib and had at least 1 postbaseline safety evaluation.
    End point type
    Secondary
    End point timeframe
    From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: Participants
    number (not applicable)
        AEs
    93
    89
        SAEs
    39
    36
    No statistical analyses for this end point

    Secondary: Summary of Plasma Concentration of Lenvatinib

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    End point title
    		 Summary of Plasma Concentration of Lenvatinib
    End point description
    Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data. The PK analysis set was used for analysis and included all participants who received at least one dose of lenvatinib and had at least one quantifiable lenvatinib concentration.
    End point type
    Secondary
    End point timeframe
    Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1)
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1 Pre-dose (n = 92, 85)
    0 ± 0
    0 ± 0
        C1D1 Post-dose (n = 89, 85)
    229.6 ± 148.98
    287.6 ± 168.97
        C1D15 Pre-dose (n = 79, 77)
    56.8 ± 82
    71.9 ± 104.09
        C1D15 Post-dose (n = 80, 79)
    284 ± 141.71
    332.1 ± 221.98
        C2D1 Pre-dose (n = 78, 73)
    38.7 ± 32.94
    52 ± 48.73
        C2D1 Post-dose (n = 74, 68)
    244.5 ± 182.67
    270.4 ± 143.64
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Concentration of Clinical Biomarkers in Whole Blood

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    End point title
    		 Change from Baseline in the Concentration of Clinical Biomarkers in Whole Blood
    End point description
    Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF). The Safety Analysis set was used and included all participants who received at least one dose of lenvatinib and had at least 1 postbaseline safety evaluation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98)
    End point values
    		 Cohort 1 (V600E BRAF negative) Cohort 2 (V600E BRAF positive)
    Number of subjects analysed
    93
    89
    Units: pg/mL
    arithmetic mean (standard deviation)
        Angiopoietin 2 76 C1D15 (n = 78, 0)
    -1015.69 ± 946.596
    0 ± 0
        Angiopoietin 2 76 C2D1 (n = 79, 0)
    -832.29 ± 1257.287
    0 ± 0
        Angiopoietin 2 76 C3D1 (n = 51, 0)
    -923.82 ± 969.285
    0 ± 0
        Angiopoietin 2 76 V98 (n = 6, 0)
    -947 ± 825.037
    0 ± 0
        Angiopoietin 2 90 C1D15 (n = 0, 69)
    0 ± 0
    -1225.32 ± 1950.453
        Angiopoietin 2 90 C2D1 (n = 0, 66)
    0 ± 0
    -1100.24 ± 1378.462
        Angiopoietin 1 C1D15 (n = 80, 70)
    -3033.03 ± 8808.206
    -2717.53 ± 16689.45
        Angiopoietin 1 C2D1 (n = 80, 67)
    -2802.31 ± 10202.78
    -1743.57 ± 15546.48
        Angiopoietin 1 C3D1 (n = 52, 0)
    -859.021 ± 9994.671
    0 ± 0
        Angiopoietin 1 V98 (n = 6, 0)
    8107.4 ± 17740.05
    0 ± 0
        Angiopoietin 2 C1D15 (n = 80, 70)
    -1462.55 ± 1541.807
    -2154.27 ± 3560.003
        Angiopoietin 2 C2D1 (n = 80, 67)
    -1225.46 ± 1872.584
    -1884.44 ± 2357.198
        Angiopoietin 2 C3D1 (n = 52, 0)
    -1255.49 ± 1738.089
    0 ± 0
        Angiopoietin 2 V98 (n = 6, 0)
    -1374.18 ± 1158.29
    0 ± 0
        CD40 Ligand C1D15 (n = 59, 70)
    -24020.8 ± 62788.25
    -4678.66 ± 41191.73
        CD40 Ligand C2D1 (n = 58, 67)
    -22957.6 ± 73677.44
    -7254.75 ± 37794.55
        CD40 Ligand C3D1 (n = 35, 0)
    -16700.9 ± 48016.07
    0 ± 0
        CD40 Ligand V98 (n = 3, 0)
    2192.177 ± 86909.97
    0 ± 0
        EGF 2 C1D15 (n = 74, 62)
    -46.493 ± 101.0772
    -0.516 ± 219.9787
        EGF 2 C2D1 (n = 76, 58)
    -39.636 ± 125.0664
    -29.803 ± 121.1705
        EGF 2 C3D1 (n = 47, 0)
    -37.6 ± 113.8543
    0 ± 0
        EGF 2 V98 (n = 6, 0)
    -2.23 ± 191.4129
    0 ± 0
        EGF 59 C1D15 (n = 77, 0)
    -37.07 ± 81.051
    0 ± 0
        EGF 59 C2D1 (n = 78, 0)
    -31.58 ± 96.2
    0 ± 0
        EGF 59 C3D1 (n = 50, 0)
    -24.49 ± 93.102
    0 ± 0
        EGF 59 V98 (n = 6, 0)
    10.17 ± 137.755
    0 ± 0
        EGF 80 C1D15 (n = 0, 65)
    0 ± 0
    -31.519 ± 126.2579
        EGF 80 C2D1 (n = 0, 65)
    0 ± 0
    -32.171 ± 121.7805
        Eotaxin-4 C1D15 (n = 78, 70)
    51.456 ± 117.1266
    46.538 ± 128.398
        Eotaxin-4 C2D1 (n = 79, 67)
    99.974 ± 207.0243
    60.919 ± 114.6134
        Eotaxin-4 C3D1 (n = 50, 0)
    89.878 ± 108.6392
    0 ± 0
        Eotaxin-4 V98 (n = 6, 0)
    104.613 ± 157.7527
    0 ± 0
        FGF 2 C1D15 (n = 77, 57)
    -4.294 ± 51.3985
    8.325 ± 136.3433
        FGF 2 C2D1 (n = 78, 54)
    -8.085 ± 48.8273
    -8.003 ± 144.9054
        FGF 2 C3D1 (n = 51, 0)
    7.443 ± 45.731
    0 ± 0
        FGF 2 V98 (n = 6, 0)
    -3.917 ± 62.3623
    0 ± 0
        FGF 23 C1D15 (n = 32, 0)
    6.549 ± 22.5297
    0 ± 0
        FGF 23 C2D1 (n = 36, 0)
    6.496 ± 27.2305
    0 ± 0
        FGF 23 C3D1 (n = 22, 0)
    6.691 ± 24.5203
    0 ± 0
        FGF 23 V98 (n = 2, 0)
    13.43 ± 36.713
    0 ± 0
        FGF 4 C1D15 (n = 68, 25)
    -24.226 ± 100.6823
    50.369 ± 253.9626
        FGF 4 C2D1 (n = 68, 23)
    -15.491 ± 104.9991
    55.785 ± 264.4585
        FGF 4 C3D1 (n = 47, 0)
    5.283 ± 130.3452
    0 ± 0
        FGF 4 V98 (n = 5, 0)
    33.86 ± 185.4616
    0 ± 0
        FGF Basic Form C1D15 (n = 68, 44)
    -0.597 ± 18.6851
    43.457 ± 224.9856
        FGF Basic Form C2D1 (n = 68, 41)
    -1.212 ± 38.4131
    64.237 ± 328.6676
        FGF Basic Form C3D1 (n = 44, 0)
    2.06 ± 29.2405
    0 ± 0
        FGF Basic Form V98 (n = 5, 0)
    18.384 ± 28.6214
    0 ± 0
        Flt3l C1D15 (n = 78, 69)
    -0.037 ± 32.5371
    -8.877 ± 23.0368
        Flt3l C2D1 (n = 79, 66)
    5.135 ± 28.0359
    -1.362 ± 39.2251
        Flt3l C3D1 (n = 51, 0)
    5.439 ± 24.1985
    0 ± 0
        Flt3l V98 (n = 6, 0)
    13.367 ± 17.7279
    0 ± 0
        Fractalkine C1D15 (n = 68, 56)
    -11.7 ± 94.5115
    38.67 ± 237.5045
        Fractalkine C2D1 (n = 69, 54)
    -1.175 ± 70.0858
    4.663 ± 58.195
        Fractalkine C3D1 (n = 47, 0)
    -5.588 ± 116.3955
    0 ± 0
        Fractalkine V98 (n = 4, 0)
    15.838 ± 90.6004
    0 ± 0
        G-CSF C1D15 (n = 78, 70)
    4.329 ± 20.8343
    6.368 ± 61.7181
        G-CSF C2D1 (n = 79, 66)
    7.366 ± 32.5552
    12.601 ± 72.5113
        G-CSF C3D1 (n = 50, 0)
    11.292 ± 24.1828
    0 ± 0
        G-CSF V98 (n = 6, 0)
    34.653 ± 101.7055
    0 ± 0
        GM-CSF C1D15 (n = 36, 26)
    0.767 ± 16.9314
    44.665 ± 220.9124
        GM-CSF C2D1 (n = 42, 27)
    4.371 ± 38.3355
    139.491 ± 725.0903
        GM-CSF C3D1 (n = 29, 0)
    10.036 ± 49.8538
    0 ± 0
        GM-CSF V98 (n = 2, 0)
    -1.495 ± 5.1831
    0 ± 0
        Growth Regulated Oncogene C1D15 (n = 0, 70)
    0 ± 0
    -141.838 ± 410.3579
        Growth Regulated Oncogene C2D1 (n = 0, 67)
    0 ± 0
    -120.148 ± 456.3073
        Hepatocyte Growth Factor C1D15 (n = 78, 68)
    102.527 ± 1309.407
    -91.79 ± 781.2225
        Hepatocyte Growth Factor C2D1 (n = 78, 65)
    -126.667 ± 693.2257
    -147.796 ± 411.1836
        Hepatocyte Growth Factor C3D1 (n = 51, 0)
    61.257 ± 1062.326
    0 ± 0
        Hepatocyte Growth Factor V98 (n = 6, 0)
    404.7 ± 456.813
    0 ± 0
        Interferon Gamma C1D15 (n = 31, 18)
    4.072 ± 19.3994
    33.743 ± 100.3678
        Interferon Gamma C2D1 (n = 32, 18)
    -0.392 ± 14.8083
    -10.164 ± 170.9869
        Interferon Gamma C3D1 (n = 21, 0)
    2.986 ± 5.7591
    0 ± 0
        Interferon Gamma V98 (n = 2, 0)
    2.455 ± 5.2255
    0 ± 0
        Interleukin 1 alpha C1D15 (n = 25, 16)
    0.159 ± 7.9441
    67.203 ± 200.9806
        Interleukin 1 alpha C2D1 (n = 28, 16)
    0.226 ± 8.2728
    -36.352 ± 198.1416
        Interleukin 1 alpha C3D1 (n = 22, 0)
    -0.14 ± 13.7136
    0 ± 0
        Interleukin 1 alpha V98 (n = 0, 0)
    0 ± 0
    0 ± 0
        Interleukin 1 Beta C1D15 (n = 16, 6)
    0.279 ± 1.9668
    59.768 ± 137.6657
        Interleukin 1 Beta C2D1 (n = 19, 6)
    1.198 ± 5.0044
    27.69 ± 61.2456
        Interleukin 1 Beta C3D1 (n = 13, 0)
    1.882 ± 11.1737
    0 ± 0
        Interleukin 1 Beta V98 (n = 0, 0)
    0 ± 0
    0 ± 0
        IL-1RA C1D15 (n = 40, 18)
    14.49 ± 63.5869
    46.381 ± 132.3985
        IL-1RA C2D1 (n = 43, 16)
    20.295 ± 61.9799
    38.131 ± 142.7521
        IL-1RA C3D1 (n = 29, 0)
    7.048 ± 30.9383
    0 ± 0
        IL-1RA V98 (N = 5, 0)
    84.614 ± 178.159
    0 ± 0
        Interleukin 12 (p40) C1D15 (n = 45, 19)
    14.514 ± 73.9806
    5.458 ± 28.8514
        Interleukin 12 (p40) C2D1 (n = 49, 19)
    16.052 ± 40.3849
    918.03 ± 3917.868
        Interleukin 12 (p40) C3D1 (n = 35, 0)
    11.183 ± 36.3506
    0 ± 0
        Interleukin 12 (p40) V98 (n = 2, 0)
    -8.13 ± 5.7276
    0 ± 0
        Interleukin 12 (p70) C1D15 (n = 17, 14)
    1.241 ± 18.8429
    27.919 ± 62.8944
        Interleukin 12 (p70) C2D1 (n = 21, 14)
    -5.622 ± 28.6381
    7.82 ± 71.1505
        Interleukin 12 (p70) C3D1 (n = 15, 0)
    -6.099 ± 19.5015
    0 ± 0
        Interleukin 12 (p70) V98 (n = 2, 0)
    11.275 ± 20.0182
    0 ± 0
        Interleukin 10 C1D15 (n = 34, 40)
    -5.17 ± 38.0092
    -7.611 ± 22.1926
        Interleukin 10 C2D1 (n = 37, 41)
    -1.901 ± 33.6203
    1.687 ± 72.7629
        Interleukin 10 C3D1 (n = 22, 0)
    4.136 ± 10.8185
    0 ± 0
        Interleukin 10 V98 (n = 2, 0)
    -28.065 ± 41.7547
    0 ± 0
        Interleukin 13 C1D15 (n = 22, 5)
    0.961 ± 5.0066
    8.574 ± 13.4754
        Interleukin 13 C2D1 (n = 23, 5)
    2.451 ± 7.6374
    8.536 ± 18.522
        Interleukin 13 C3D1 (n = 17, 0)
    5.404 ± 16.4719
    0 ± 0
        Interleukin 13 V98 (n = 0, 0)
    0 ± 0
    0 ± 0
        Interleukin 15 C1D15 (n = 21, 8)
    0.128 ± 2.2957
    85.619 ± 234.7106
        Interleukin 15 C2D1 (n = 23, 9)
    1.403 ± 4.163
    574.776 ± 1709.927
        Interleukin 15 C3D1 (n = 16, 0)
    -0.178 ± 3.6993
    0 ± 0
        Interleukin 15 V98 (n = 1, 0)
    3.93 ± 3.93
    0 ± 0
        Interleukin 17 C1D15 (n = 24, 9)
    3.434 ± 8.6463
    4.567 ± 12.1008
        Interleukin 17 C2D1 (n = 24, 11)
    1.264 ± 8.0963
    3.035 ± 15.8736
        Interleukin 17 C3D1 (n = 15, 0)
    0.011 ± 3.41
    0 ± 0
        Interleukin 17 V98 (n = 2, 0)
    8.44 ± 11.7663
    0 ± 0
        Interleukin 2 C1D15 (n = 14, 6)
    -1.004 ± 7.1024
    173.878 ± 397.2754
        Interleukin 2 C2D1 (n = 9, 6)
    5.853 ± 20.3294
    191.41 ± 461.1991
        Interleukin 2 C3D1 (n = 11, 0)
    2.647 ± 19.5979
    0 ± 0
        Interleukin 2 V98 (n = 0, 0)
    0 ± 0
    0 ± 0
        Interleukin 4 C1D15 (n = 23, 39)
    8.169 ± 30.0305
    12.815 ± 77.431
        Interleukin 4 C2D1 (n = 23, 40)
    20.167 ± 77.0619
    7.815 ± 54.5735
        Interleukin 4 C3D1 (n = 20, 0)
    6.583 ± 20.3824
    0 ± 0
        Interleukin 4 V98 (n = 0, 0)
    0 ± 0
    0 ± 0
        Interleukin 5 C1D15 (n = 9, 5)
    0.311 ± 1.1314
    6.088 ± 7.5239
        Interleukin 5 C2D1 (n = 10, 6)
    0.205 ± 1.5931
    11.382 ± 9.8663
        Interleukin 5 C3D1 (n = 6, 0)
    -0.327 ± 1.1102
    0 ± 0
        Interleukin 6 C1D15 (n = 35, 39)
    0.166 ± 6.8774
    3.784 ± 30.0715
        Interleukin 6 C2D1 (n = 34, 36)
    4.778 ± 34.0254
    5.524 ± 32.1205
        Interleukin 6 C3D1 (n = 21, 0)
    2.027 ± 7.3121
    0 ± 0
        Interleukin 6 V98 (n = 4, 0)
    3.16 ± 6.6276
    0 ± 0
        Interleukin 7 C1D15 (n = 26, 20)
    1.267 ± 7.3732
    2.167 ± 8.8122
        Interleukin 7 C2D1 (n = 28, 21)
    2.413 ± 8.8367
    5.744 ± 18.4339
        Interleukin 7 C3D1 (n = 19, 0)
    0.616 ± 5.059
    0 ± 0
        Interleukin 7 V98 (n = 2, 0)
    20.76 ± 28.0439
    0 ± 0
        Interleukin 8 C1D15 (n = 78, 68)
    -5.801 ± 46.1572
    -20.769 ± 52.1135
        Interleukin 8 C2D1 (n = 79, 65)
    -5.431 ± 43.4197
    -14.303 ± 57.9561
        Interleukin 8 C3D1 (n = 50, 0)
    -7.348 ± 43.0509
    0 ± 0
        Interleukin 8 V98 (n = 6, 0)
    26.982 ± 32.7795
    0 ± 0
        IFN gamma Induced Protein 10 C1D15 (n = 78, 70)
    453.684 ± 1446.583
    184.891 ± 501.5782
        IFN gamma Induced Protein 10 C2D1 (n = 79, 67)
    246.194 ± 337.6926
    306.075 ± 792.5621
        IFN gamma Induced Protein 10 C3D1 (n = 50, 0)
    201.923 ± 483.5088
    0 ± 0
        IFN gamma Induced Protein 10 V98 (n = 6, 0)
    359.872 ± 501.1082
    0 ± 0
        Monocyte Chemotactic Protein 1 C1D15 (n = 78, 70)
    0.733 ± 423.2721
    -101.58 ± 371.5381
        Monocyte Chemotactic Protein 1 C2D1 (n = 79, 67)
    -19.036 ± 372.5242
    128.749 ± 541.1034
        Monocyte Chemotactic Protein 1 C3D1 (n = 50, 0)
    13.542 ± 370.37
    0 ± 0
        Monocyte Chemotactic Protein 1 V98 (n = 6, 0)
    -128.627 ± 1234.589
    0 ± 0
        MIP 1 alpha C1D15 (n = 76, 51)
    -1.842 ± 11.9129
    -0.32 ± 38.5273
        MIP 1 alpha C2D1 (n = 76, 46)
    -2.098 ± 12.0121
    -0.473 ± 35.4447
        MIP 1 alpha C3D1 (n = 49, 0)
    -1.167 ± 15.9038
    0 ± 0
        MIP 1 alpha V98 (n = 6, 0)
    7.563 ± 7.8802
    0 ± 0
        MIP 1 beta C1D15 (n = 78, 70)
    0.032 ± 20.149
    5.746 ± 64.1386
        MIP 1 beta C2D1 (n = 79, 67)
    -1.198 ± 31.1522
    31.277 ± 261.346
        MIP 1 beta C3D1 (n = 50, 0)
    1.85 ± 15.208
    0 ± 0
        MIP 1 beta V98 (n = 6, 0)
    7.518 ± 11.9566
    0 ± 0
        PDGF AA 31 P1 C1D15 (n = 0, 69)
    0 ± 0
    -183.36 ± 2260.11
        PDGF AA 31 P1 C2D1 (n = 0, 66)
    0 ± 0
    -268.83 ± 2054.666
        PDGF AB C1D15 (n = 76, 69)
    -36.637 ± 353.6898
    -121.278 ± 325.1308
        PDGF AB C2D1 (n = 77, 66)
    -99.852 ± 338.5816
    -80.778 ± 363.1249
        PDGF AB C3D1 (n = 50, 0)
    -7.702 ± 311.6834
    0 ± 0
        PDGF AB V98 (n = 5, 0)
    130.8 ± 382.6282
    0 ± 0
        PDGF BB C1D15 (n = 78, 69)
    -120.317 ± 1758.765
    -567.664 ± 1385.674
        PDGF BB C2D1 (n = 79, 66)
    -435.311 ± 1961.744
    -371.888 ± 1186.644
        PDGF BB C3D1 (n =51, 0)
    333.637 ± 1516.15
    0 ± 0
        PDGF BB V98 (n = 6, 0)
    174.083 ± 3221.901
    0 ± 0
        Placental Derived Growth Factor C1D15 (n = 78, 56)
    55.444 ± 55.0671
    26.465 ± 29.8457
        Placental Derived Growth Factor C2D1 (n = 79, 54)
    50.439 ± 58.2571
    51.359 ± 76.639
        Placental Derived Growth Factor C3D1 (n = 51, 0)
    61.08 ± 58.2969
    0 ± 0
        Placental Derived Growth Factor V98 (n = 6, 0)
    112.683 ± 110.3416
    0 ± 0
        Chemokine Ligand 5 C1D15 (n = 0, 70)
    0 ± 0
    -2373.94 ± 46225.7
        Chemokine Ligand 5 C1D15 C2D1 (n = 0, 67)
    0 ± 0
    551.64 ± 49492.45
        SDF 1 alpha C1D15 (n = 77, 69)
    441.305 ± 385.8988
    506.768 ± 487.7603
        SDF 1 alpha C2D1 (n = 77, 66)
    520.051 ± 510.8558
    647.435 ± 470.0962
        SDF 1 alpha C3D1 (n = 51, 0)
    509.483 ± 550.4383
    0 ± 0
        SDF 1 alpha V98 (n = 5, 0)
    836.532 ± 686.4434
    0 ± 0
        Soluble IL2 Receptor alpha C1D15 (n = 65, 67)
    -25.869 ± 86.0991
    -414.669 ± 765.1544
        Soluble IL2 Receptor alpha C2D1 (n = 67, 64)
    -13.695 ± 65.5643
    -290.918 ± 1023.339
        Soluble IL2 Receptor alpha C3D1 (n = 41, 0)
    -12.233 ± 31.5415
    0 ± 0
        Soluble IL2 Receptor alpha V98 (n = 4, 0)
    -19.238 ± 43.0942
    0 ± 0
        TGF alpha C1D15 (n = 52, 48)
    -0.874 ± 4.6605
    21.148 ± 168.7766
        TGF alpha C2D1 (n = 51, 43)
    -0.35 ± 6.5375
    -6.019 ± 24.3258
        TGF alpha C3D1 (n = 31, 0)
    1.165 ± 11.8825
    0 ± 0
        TGF alpha V98 (n = 3, 0)
    2.59 ± 3.4672
    0 ± 0
        Tie-2 C1D15 (n = 77, 69)
    -2971.95 ± 2397.523
    -3573.86 ± 2996.714
        Tie-2 C2D1 (n = 78, 66)
    -3447.69 ± 3577.179
    -4088.21 ± 3191.981
        Tie-2 C3D1 (n = 51, 0)
    -2811.77 ± 3459.193
    0 ± 0
        Tie-2 V98 (n = 5, 0)
    -1924 ± 3215.568
    0 ± 0
        TNF alpha C1D15 (n = 77, 67)
    -0.233 ± 4.9747
    1.451 ± 24.8216
        TNF alpha C2D1 (n = 78, 64)
    0.039 ± 3.954
    1.741 ± 15.0677
        TNF alpha C3D1 (n = 49, 0)
    0.614 ± 4.6336
    0 ± 0
        TNF alpha V98 (n = 6, 0)
    3.027 ± 4.7343
    0 ± 0
        VEGF C1D15 (n = 78, 66)
    -13.294 ± 112.6871
    10.709 ± 285.2533
        VEGF C2D1 (n = 78, 62)
    -11.523 ± 122.6064
    -26.215 ± 239.496
        VEGF C3D1 (n = 50, 0)
    16.732 ± 160.3096
    0 ± 0
        VEGF V98 (n = 6, 0)
    155.638 ± 352.8309
    0 ± 0
        VEGF A C1D15 (n = 78, 69)
    78.868 ± 174.8011
    92.748 ± 273.619
        VEGF A C2D1 (n = 79, 66)
    76.041 ± 194.1394
    140.664 ± 336.9135
        VEGF A C3D1 (n = 51, 0)
    116.8 ± 233.1657
    0 ± 0
        VEGF A V98 (n = 6, 0)
    465.833 ± 515.7676
    0 ± 0
        VEGF D C1D15 (n = 78, 21)
    0.953 ± 87.6513
    3.404 ± 42.7585
        VEGF D C2D1 (n = 78, 19)
    -9.776 ± 98.0905
    11.043 ± 116.5445
        VEGF D C3D1 (n = 51, 0)
    9.894 ± 57.114
    0 ± 0
        VEGF D V98 (n = 6, 0)
    -21.317 ± 88.6689
    0 ± 0
        VEGF Rec 1 C1D15 (n = 78, 55)
    593.613 ± 3109.334
    -221.867 ± 799.9202
        VEGF Rec 1 C2D1 (n = 79, 53)
    -3.971 ± 739.7875
    -243.661 ± 1031.237
        VEGF Rec 1 C3D1 (n = 51, 0)
    -209.863 ± 809.7744
    0 ± 0
        VEGF Rec 1 V98 (n = 6, 0)
    -15.567 ± 90.6274
    0 ± 0
        VEGF Rec 2 C1D15 (n = 78, 67)
    -10110.1 ± 5626.013
    -8842.04 ± 6078.715
        VEGF Rec 2 C2D1 (n = 78, 64)
    -9369.17 ± 17982.06
    -10676.6 ± 7064.083
        VEGF Rec 2 C3D1 (n = 51, 0)
    -11389.6 ± 10955.16
    0 ± 0
        VEGF Rec 2 V98 (n = 6, 0)
    -9021.22 ± 5921.962
    0 ± 0
        VEGF Rec 3 C1D15 (n = 70, 61)
    -1174.65 ± 2226.789
    -2251.87 ± 3231.149
        VEGF Rec 3 C2D1 (n = 68, 58)
    -1320.73 ± 3138.381
    -2523.26 ± 3550.729
        VEGF Rec 3 C3D1 (n = 47, 0)
    -1488.14 ± 3687.877
    0 ± 0
        VEGF Rec 3 V98 (n = 5, 0)
    -1201.68 ± 2441.574
    0 ± 0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Cohort 1 (V600E BRAF Negative)
    Reporting group description
    		 Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.

    Reporting group title
    Cohort 2 (V600E BRAF Positive)
    Reporting group description
    		 Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.

    Serious adverse events
    		 Cohort 1 (V600E BRAF Negative) Cohort 2 (V600E BRAF Positive)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 93 (41.94%)
    36 / 89 (40.45%)
         number of deaths (all causes)
    42
    64
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Infected neoplasm
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 93 (3.23%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Impaired healing
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical peritonitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial thrombosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve palsies multiple
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 93 (3.23%)
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 (V600E BRAF Negative) Cohort 2 (V600E BRAF Positive)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 93 (100.00%)
    88 / 89 (98.88%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 89 (1.12%)
         occurrences all number
    5
    1
    Hypotension
         subjects affected / exposed
    4 / 93 (4.30%)
    6 / 89 (6.74%)
         occurrences all number
    4
    7
    Hypertension
         subjects affected / exposed
    53 / 93 (56.99%)
    48 / 89 (53.93%)
         occurrences all number
    111
    88
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 93 (6.45%)
    5 / 89 (5.62%)
         occurrences all number
    7
    12
    Chills
         subjects affected / exposed
    6 / 93 (6.45%)
    4 / 89 (4.49%)
         occurrences all number
    6
    4
    Fatigue
         subjects affected / exposed
    62 / 93 (66.67%)
    41 / 89 (46.07%)
         occurrences all number
    109
    66
    Oedema peripheral
         subjects affected / exposed
    14 / 93 (15.05%)
    10 / 89 (11.24%)
         occurrences all number
    17
    11
    Pain
         subjects affected / exposed
    6 / 93 (6.45%)
    5 / 89 (5.62%)
         occurrences all number
    7
    5
    Pyrexia
         subjects affected / exposed
    7 / 93 (7.53%)
    10 / 89 (11.24%)
         occurrences all number
    10
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 93 (19.35%)
    11 / 89 (12.36%)
         occurrences all number
    19
    11
    Dysphonia
         subjects affected / exposed
    26 / 93 (27.96%)
    33 / 89 (37.08%)
         occurrences all number
    32
    35
    Dyspnoea
         subjects affected / exposed
    14 / 93 (15.05%)
    13 / 89 (14.61%)
         occurrences all number
    16
    13
    Epistaxis
         subjects affected / exposed
    8 / 93 (8.60%)
    8 / 89 (8.99%)
         occurrences all number
    9
    8
    Oropharyngeal pain
         subjects affected / exposed
    13 / 93 (13.98%)
    5 / 89 (5.62%)
         occurrences all number
    13
    5
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 93 (2.15%)
    5 / 89 (5.62%)
         occurrences all number
    2
    7
    Depression
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 89 (5.62%)
         occurrences all number
    4
    8
    Insomnia
         subjects affected / exposed
    7 / 93 (7.53%)
    8 / 89 (8.99%)
         occurrences all number
    8
    8
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 93 (3.23%)
    5 / 89 (5.62%)
         occurrences all number
    3
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 93 (7.53%)
    3 / 89 (3.37%)
         occurrences all number
    10
    4
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    14 / 93 (15.05%)
    7 / 89 (7.87%)
         occurrences all number
    20
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 89 (1.12%)
         occurrences all number
    7
    1
    Lipase increased
         subjects affected / exposed
    7 / 93 (7.53%)
    3 / 89 (3.37%)
         occurrences all number
    19
    3
    Weight decreased
         subjects affected / exposed
    22 / 93 (23.66%)
    12 / 89 (13.48%)
         occurrences all number
    24
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 93 (10.75%)
    16 / 89 (17.98%)
         occurrences all number
    12
    19
    Dysgeusia
         subjects affected / exposed
    12 / 93 (12.90%)
    16 / 89 (17.98%)
         occurrences all number
    15
    18
    Headache
         subjects affected / exposed
    29 / 93 (31.18%)
    21 / 89 (23.60%)
         occurrences all number
    37
    25
    Lethargy
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 89 (5.62%)
         occurrences all number
    1
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    10 / 93 (10.75%)
    2 / 89 (2.25%)
         occurrences all number
    11
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 93 (5.38%)
    6 / 89 (6.74%)
         occurrences all number
    8
    13
    Thrombocytopenia
         subjects affected / exposed
    8 / 93 (8.60%)
    9 / 89 (10.11%)
         occurrences all number
    9
    15
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    21 / 93 (22.58%)
    19 / 89 (21.35%)
         occurrences all number
    27
    23
    Abdominal pain upper
         subjects affected / exposed
    11 / 93 (11.83%)
    6 / 89 (6.74%)
         occurrences all number
    13
    7
    Constipation
         subjects affected / exposed
    25 / 93 (26.88%)
    28 / 89 (31.46%)
         occurrences all number
    30
    34
    Diarrhoea
         subjects affected / exposed
    44 / 93 (47.31%)
    26 / 89 (29.21%)
         occurrences all number
    89
    52
    Dry mouth
         subjects affected / exposed
    14 / 93 (15.05%)
    10 / 89 (11.24%)
         occurrences all number
    14
    10
    Dyspepsia
         subjects affected / exposed
    5 / 93 (5.38%)
    9 / 89 (10.11%)
         occurrences all number
    6
    15
    Flatulence
         subjects affected / exposed
    12 / 93 (12.90%)
    2 / 89 (2.25%)
         occurrences all number
    16
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 93 (10.75%)
    6 / 89 (6.74%)
         occurrences all number
    10
    8
    Glossodynia
         subjects affected / exposed
    6 / 93 (6.45%)
    2 / 89 (2.25%)
         occurrences all number
    6
    2
    Nausea
         subjects affected / exposed
    48 / 93 (51.61%)
    36 / 89 (40.45%)
         occurrences all number
    64
    45
    Oral pain
         subjects affected / exposed
    10 / 93 (10.75%)
    5 / 89 (5.62%)
         occurrences all number
    14
    5
    Stomatitis
         subjects affected / exposed
    16 / 93 (17.20%)
    12 / 89 (13.48%)
         occurrences all number
    27
    21
    Vomiting
         subjects affected / exposed
    36 / 93 (38.71%)
    32 / 89 (35.96%)
         occurrences all number
    56
    49
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    16 / 93 (17.20%)
    7 / 89 (7.87%)
         occurrences all number
    17
    7
    Pruritus
         subjects affected / exposed
    7 / 93 (7.53%)
    5 / 89 (5.62%)
         occurrences all number
    8
    6
    Rash
         subjects affected / exposed
    16 / 93 (17.20%)
    5 / 89 (5.62%)
         occurrences all number
    18
    6
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 93 (5.38%)
    3 / 89 (3.37%)
         occurrences all number
    5
    5
    Proteinuria
         subjects affected / exposed
    23 / 93 (24.73%)
    17 / 89 (19.10%)
         occurrences all number
    48
    34
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    17 / 93 (18.28%)
    24 / 89 (26.97%)
         occurrences all number
    20
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 93 (31.18%)
    20 / 89 (22.47%)
         occurrences all number
    37
    32
    Back pain
         subjects affected / exposed
    17 / 93 (18.28%)
    12 / 89 (13.48%)
         occurrences all number
    19
    15
    Muscle spasms
         subjects affected / exposed
    7 / 93 (7.53%)
    5 / 89 (5.62%)
         occurrences all number
    8
    5
    Muscular weakness
         subjects affected / exposed
    8 / 93 (8.60%)
    3 / 89 (3.37%)
         occurrences all number
    11
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 89 (6.74%)
         occurrences all number
    7
    8
    Musculoskeletal pain
         subjects affected / exposed
    6 / 93 (6.45%)
    6 / 89 (6.74%)
         occurrences all number
    8
    9
    Musculoskeletal stiffness
         subjects affected / exposed
    7 / 93 (7.53%)
    4 / 89 (4.49%)
         occurrences all number
    10
    8
    Myalgia
         subjects affected / exposed
    13 / 93 (13.98%)
    9 / 89 (10.11%)
         occurrences all number
    16
    12
    Pain in extremity
         subjects affected / exposed
    16 / 93 (17.20%)
    9 / 89 (10.11%)
         occurrences all number
    18
    12
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    5 / 93 (5.38%)
    0 / 89 (0.00%)
         occurrences all number
    5
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 93 (5.38%)
    4 / 89 (4.49%)
         occurrences all number
    5
    4
    Urinary tract infection
         subjects affected / exposed
    10 / 93 (10.75%)
    9 / 89 (10.11%)
         occurrences all number
    13
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    40 / 93 (43.01%)
    30 / 89 (33.71%)
         occurrences all number
    51
    41
    Dehydration
         subjects affected / exposed
    6 / 93 (6.45%)
    12 / 89 (13.48%)
         occurrences all number
    6
    12
    Hypokalaemia
         subjects affected / exposed
    6 / 93 (6.45%)
    2 / 89 (2.25%)
         occurrences all number
    7
    2
    Hyponatraemia
         subjects affected / exposed
    8 / 93 (8.60%)
    4 / 89 (4.49%)
         occurrences all number
    8
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jan 2011
    1) clarified each cohort population, allowed up to 2 prior regimens for Cohort 1 and any activating BRAF mutation (mainly V600E) for Cohort 2 2) changed study design to Simon’s Optimal 2-Stage Design, which would have allowed for early termination of study if response was not sufficient 3) provided lesion size specifications for single lesion only 4) added criterion allowing subjects with brain metastases under specified circumstances 5) renal function requirement updated from 30 mL/min to 40 mL/min 6) clarified interruption/dose reduction for anemia, lymphocytopenia, and neutropenia. Reasons for changes: Clarified study population for each cohort regarding BRAF activating mutations and allowed number of prior anticancer therapies. Relaxing allowed number of prior treatments reflected a more contemporaneous approach regarding prior treatments a subject was exposed to for Stage III or IV unresectable melanoma. Also, amended entry criterion allowed for an improved enrollment rate without any detriment on the ability to assess the effect of lenvatinib on the 2 distinct study populations. Simon’s Optimal 2-Stage Design was introduced to address questions/criticism from multiple sites and/or scientific committees/IRBs of not having means to control the study population exposure to lenvatinib in the event it was shown not to be efficacious in the study population. Entry criteria changed to allow subjects with brain metastasis under specific circumstances per the current understanding that a select population of subjects with brain metastasis (resected, asymptomatic disease and free of new metastasis) are good candidates for clinical trials and may equally benefit from participation in experimental clinical studies. Renal function requirement updated to reflect current understanding of lenvatinib potential for nephrotoxicity. Dose modification guidelines assessed more conservatively hematologic toxicities (anemia, neutropenia, lymphocytopenia) related to lenvatinib.
    16 Mar 2012
    Amendment 02: (1)Added exception to exclusion of timing of prior chemotherapy within 21 days, within 14 days allowed in subjects with rapid progression while receiving BRAF-targeted therapy. Reason for the change is as follows: The added language pertains to the Cohort 2 population, i.e., subjects who have a BRAF mutation and who failed a BRAF-targeted therapy. For these subjects there are no other effective treatment options and their disease is rapidly progressing once they fail the BRAF-targeted therapy.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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