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    Clinical Trial Results:
    A phase II, multi-center, open-label study of single-agent LGX818 followed by a rational combination with targeted agents after progression on LGX818, to overcome resistance in adult patients with locally advanced or metastatic BRAF V600 melanoma

    Summary
    EudraCT number
    		 2012-004798-17
    Trial protocol
    		 ES   DE  
    Global end of trial date
    23 Mar 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CLGX818X2102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01820364
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov: NCT01820364
    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
    23 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a phase II, two-part, multi-center, open-label study in adult patients with locally advanced unresectable or metastatic BRAFV600-mutant melanoma. Part I: LGX818 single-agent treatment in BRAF inhibitor-naive patients. Part II: Combination treatments of LGX818 + MEK162, or BKM120, or BGJ398, or INC280, or LEE011 to assess the clinical efficacy and to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic BRAF-mutant melanoma after relapse on LGX818. These drug combinations were selected based on documentation of molecular resistance mechanism. Patients with BRAF-mutant melanoma treated with single agent LGX818 in other studies could be enrolled directly in part II of CLGX818X2102 after relapse and documentation of progression.
    Protection of trial subjects
    Patients had to provide a signed molecular pre-screening informed consent form (ICF) for any study-related molecular pre-screening procedure. After the mutational status of BRAF was known or determined, the patient was allowed to sign the main study ICF prior to any study-specific screening evaluations. The study was described by the Investigator or designee, who answered any questions, and written information was also provided.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    24 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    15
    EEA total number of subjects
    4
    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)
    12
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment began on 24-Jun-2013 to the CLGX818X2102 (LOGIC 1) study. A total of 15 subjects were enrolled. The last subject's last visit occurred on 23-Mar-2015. Not completed subjects represents subjects that stopped treatment early, due to the corresponding reason.

    Pre-assignment
    Screening details
    		 N/A

    Period 1
    Period 1 title
    Part I: LGX818
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study. Therefore, blinding implementation details are not applicable.

    Arms
    Arm title
    		 Part I: LGX818 - single agent
    Arm description
    		 Subjects in Part I of the study received LGX818 as a single agent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg QD, (21-day cycles)

    Number of subjects in period 1
    		Part I: LGX818 - single agent
    Started
    15
    Completed
    1
    Not completed
    14
         Disease progression
    4
         Adverse event, non-fatal
    6
         Death
    1
         Administrative problems
    3
    Period 2
    Period 2 title
    Part II: LGX818 + MEK162
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study. Therefore, blinding implementation details are not applicable.

    Arms
    Arm title
    		 Part II: CLGX818 + MEK162
    Arm description
    		 As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    450 mg QD, (21-day cycles)

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    MEK162
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg QD, (21-day cycles)

    Number of subjects in period 2
    		Part II: CLGX818 + MEK162
    Started
    1
    Completed
    0
    Not completed
    1
         Study termination
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part I: LGX818
    Reporting group description
    		 Subjects in Part I of the study received LGX818 - single agent.

    Reporting group values
    		 Part I: LGX818 Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 12 12
        From 65-84 years
    		 3 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ± 16.53 -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 8 8
    WHO/ ECOG performance status
    Categories 0 - Fully active, able to carry on all pre-disease performance without restriction. 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, 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
        Category 0
    		 14 14
        Category 1
    		 1 1
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 80.3 ± 19.11 -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 171.8 ± 9.51 -

    End points

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    End points reporting groups
    Reporting group title
    Part I: LGX818 - single agent
    Reporting group description
    		 Subjects in Part I of the study received LGX818 as a single agent.
    Reporting group title
    Part II: CLGX818 + MEK162
    Reporting group description
    		 As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.

    Primary: Tumor Response (Overall Response Rate) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)

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    End point title
    		 Tumor Response (Overall Response Rate) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) [1]
    End point description
    Objective response rate (ORR) was not evaluated due to an inadequate number of patients enrolled in part II prior to the permanent recruitment halt of this study. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was collected for this end point.
    End point type
    Primary
    End point timeframe
    Baseline through study completion (approximately 3 years)
    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: Objective response rate (ORR) was not evaluated due to an inadequate number of patients enrolled in part II prior to the permanent recruitment halt of this study.
    End point values
    		 Part I: LGX818 - single agent Part II: CLGX818 + MEK162
    Number of subjects analysed
    15
    1
    Units: Percentage of Subjects
        Not Applicable
    999
    999
    No statistical analyses for this end point

    Secondary: Incidence of Dose Limiting Toxicities (DLTs) (Part II)

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    End point title
    		 Incidence of Dose Limiting Toxicities (DLTs) (Part II)
    End point description
    Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was collected for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline through study completion (approximately 3 years)
    End point values
    		 Part II: CLGX818 + MEK162
    Number of subjects analysed
    1
    Units: DLTs
        Not Applicable
    999
    No statistical analyses for this end point

    Secondary: Plasma Concentration and Derived Pharmacokinetic Parameters

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    End point title
    		 Plasma Concentration and Derived Pharmacokinetic Parameters
    End point description
    Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was collected for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline through study completion (approximately 3 years)
    End point values
    		 Part I: LGX818 - single agent Part II: CLGX818 + MEK162
    Number of subjects analysed
    15
    1
    Units: N/A
    arithmetic mean (standard deviation)
        Not Applicable
    999 ± 999
    999 ± 999
    No statistical analyses for this end point

    Secondary: Tumor Response (Overall Response Rate) via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)

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    End point title
    		 Tumor Response (Overall Response Rate) via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)
    End point description
    Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: - Complete Response (CR) is the Disappearance of all target lesions. - Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. - Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. - Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
    End point type
    Secondary
    End point timeframe
    Baseline through completion of Part I of the study
    End point values
    		 Part I: LGX818 - single agent
    Number of subjects analysed
    15 [2]
    Units: Subjects
        Complete Response
    1
        Partial Response
    8
        Progressive Disease
    1
        Stable Disease
    2
        Unknown
    3
    Notes
    [2] - Full Analysis Set, which consists of all patients who received at least one dose of LGX818.
    No statistical analyses for this end point

    Secondary: Tumor Response (Overall Response Rate) via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)

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    End point title
    		 Tumor Response (Overall Response Rate) via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)
    End point description
    Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: - Complete Response (CR) is the Disappearance of all target lesions. - Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. - Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. - Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.
    End point type
    Secondary
    End point timeframe
    Entry to Part II of the study through study completion (approximately 22 days)
    End point values
    		 Part II: CLGX818 + MEK162
    Number of subjects analysed
    1 [3]
    Units: Subjects
        Progressive Disease
    1
    Notes
    [3] - Full Analysis Set, which consists of all patients who received at least one dose of LGX818.
    No statistical analyses for this end point

    Secondary: Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways

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    End point title
    		 Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways
    End point description
    Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study. As EudraCT only allows numerical data entry, the value of 999 indicates "No Value", as no data was collected for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and at progression with LGX818 single agent treatment
    End point values
    		 Part I: LGX818 - single agent Part II: CLGX818 + MEK162
    Number of subjects analysed
    15
    1
    Units: N/A
    arithmetic mean (standard deviation)
        Not Applicable
    999 ± 999
    999 ± 999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events, Serious Adverse Events, and Non-serious Adverse Events were collected throughout the duration of the study. Enrollment to the study began on 24-Jun-2013 and the study ended on 23-Mar-2015.
    Adverse event reporting additional description
    An Adverse Event was 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
    16.1
    Reporting groups
    Reporting group title
    Safety Set
    Reporting group description
    		 The analysis group for Adverse Event, Serious Adverse Event, and Non-serious Adverse Event reporting is the Safety Set. The Safety Set consists of all patients from the Full Analysis Set who had at least one post-baseline safety assessment.

    Serious adverse events
    		 Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases To Central Nervous System
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Panic Attack
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal Failure Acute
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic Naevus
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Skin Papilloma
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Acrochordon
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blepharal Papilloma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pyogenic Granuloma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Seborrhoeic Keratosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 15 (60.00%)
         occurrences all number
    9
    Asthenia
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Oedema Peripheral
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Face Oedema
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Breast Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Menstruation Irregular
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vaginal Haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Investigations
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Amylase Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood Cholesterol Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haemoglobin Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Lipase Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Weight Decreased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Procedural Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Toxicity To Various Agents
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Long Qt Syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Aphasia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Convulsion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypogeusia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Neuralgia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Peripheral Sensorimotor Neuropathy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    VIIth Nerve Paralysis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    10 / 15 (66.67%)
         occurrences all number
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    5
    Leukocytosis
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Eosinophilia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Conjunctival Hyperaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Ophthalmoplegia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vision Blurred
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gingival Bleeding
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Inguinal Hernia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tongue Coated
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Hyperkeratosis
         subjects affected / exposed
    12 / 15 (80.00%)
         occurrences all number
    12
    Alopecia
         subjects affected / exposed
    10 / 15 (66.67%)
         occurrences all number
    10
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    9 / 15 (60.00%)
         occurrences all number
    9
    Dry Skin
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Rash Maculo-Papular
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Erythema
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Rash Papular
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Granuloma Skin
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Palmar Erythema
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Papule
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash Macular
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin Hypertrophy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haematuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    6
    Myalgia
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Back Pain
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Muscular Weakness
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Musculoskeletal Pain
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Joint Swelling
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pain In Extremity
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Anal Abscess
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Folliculitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Oral Candidiasis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Hyperglycaemia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Dehydration
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2013
    Amendment 1 consisted of the following revisions: • Safety results from a Phase 1 study of LGX818 as a single agent (Study CLGX818X2101) resulted in a RP2D for LGX818 single-agent of 300 mg/day. Updated safety data were added and the LGX818 starting dose was adjusted accordingly from 450 mg/day to 300 mg/day. • Safety results from a Phase 1 study of INC280 as a single agent (CINC280X2102) resulted in a revised starting dose for INC280. • Inclusion criteria for Part II were modified to define the refractory or resistant study population. • Criteria were added to define which patients were eligible to continue to receive LGX818 single agent after progression and during the analysis of their tumor biopsy and subsequent assignment to a combination arm in Part II.
    15 Jul 2013
    Amendment 2 consisted of the following revisions: • Hypomagnesaemia was added to exclusion criteria 25 and 28 and it was clarified that magnesium had to be within clinically relevant limits.
    19 Dec 2013
    Amendment 3 consisted of the following revisions: • Routine ophthalmic examinations were implemented at baseline, Day 85 (Cycle 4 Day 1 for 28-day cycles; Cycle 5 Day 1 for 21 day cycles), every 12 weeks thereafter, end of treatment and as clinically indicated in order to monitor the potential risk of retinal/ocular changes and included recommendations for LGX818 dose modifications for visual toxicity. • Definitions of ophthalmologic DLTs were provided.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Jul 2014
    Due to slow enrolment and after careful evaluation of the recent development in the treatment landscape of the patients with BRAF-mutant melanoma, recruitment was permanently halted on 26-Jul-2014 and a total of 15 patients were treated in the study. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per 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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    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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