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    Clinical Trial Results:
    LGX818 in combination with MEK162 in refractory or relapsed multiple myeloma patients with BRAFV600E or BRAFV600K mutation

    Summary
    EudraCT number
    		 2014-004597-42
    Trial protocol
    		 DE  
    Global end of trial date
    30 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2024
    First version publication date
    10 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BIRMA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02834364
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universtity Hospital Heidelberg
    Sponsor organisation address
    Im Neuenheimer Feld 672, Heidelberg, Germany, 69120
    Public contact
    Internal Medicine V, University Hospital Heidelberg, +49 6221564781, marc.raab@med.uni-heidelberg.de
    Scientific contact
    Internal Medicine V, University Hospital Heidelberg, +49 6221564781, marc.raab@med.uni-heidelberg.de
    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
    21 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the therapeutic efficacy of LGX818/MEK162 to decrease myeloma tumour burden
    Protection of trial subjects
    If, in the investigator’s opinion, continuation of the trial would be detrimental to the subject’s well-being, the trial participation would have been stopped. Recommendations to modify dose in case of treatment-related adverse events were included in the protocol. Specific measures were defined for management of hand foot skin reaction, nausea and vomiting, blood pressure management, management of opthalmological events, follow up evaluations for keratoacanthoma and/or squamous cell carcinoma.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2016
    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
    Germany: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    8
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited at 4 different sites in Germany.

    Pre-assignment
    Screening details
    		 Patients with relapsed or refractory Multiple Myeloma after failure of at least two treatment regimens and with BRAFV600E/K mutation were examined for in- and exclusion criteria.

    Period 1
    Period 1 title
    Therapy (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    In this single arm study no blinding was performed.

    Arms
    Arm title
    		 Therapy
    Arm description
    		 Patients with relaped or refractory Multiple Myeloma with BRAF V600E/K-mutation were treated with LGX818/MEK162
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    L01EC03
    Other name
    LGY818, Braftovi
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    450 mg p.o.once daily

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    L01EE03
    Other name
    MEK162, Mektovi
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg p.o. twice daily

    Number of subjects in period 1
    		Therapy
    Started
    12
    Completed
    12

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Therapy
    Reporting group description
    		 Patients with relaped or refractory Multiple Myeloma with BRAF V600E/K-mutation were treated with LGX818/MEK162

    Primary: Overall Response Rate

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    End point title
    		 Overall Response Rate [1]
    End point description
    The primary objective of this study is to demonstrate the therapeutic efficacy of LGX818/MEK162 to decrease myeloma tumour burden. The overall response rate (ORR) is defined as the percentage of patients that achieved a minimal response (MR) or better within a time period of 1 year after start of study drug treatment. Best response will be used to calculate ORR.
    End point type
    Primary
    End point timeframe
    Completion of at least one cycle of 28 days LGX818/MEK162
    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: There was no control arm. A null hypothesis tested in the EP population was H0: ORR > 20% against the alternative H1: ORR > 20% using a one-sided binomial test with significance level 5%. For this analysis, missing response data would have been counted as non-responders. An effect estimate of 0.833 was calculated with a lower 95% confidence boudars 0f 0.592 (p=0.00).
    End point values
    		 Therapy
    Number of subjects analysed
    12
    Units: patients
        stable disease
    2
        partial response
    4
        very good partial response
    3
        near complete response
    2
        complete response
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During therapy
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    safety population
    Reporting group description
    		 All patients were followed in weekly intervals during the first cycle, in cycle 2 week 2 and week 4, thereafter in 28 day intervals.

    Serious adverse events
    		 safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    9
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    7
    Psychiatric disorders
    Psychiatric disorders
    Additional description: insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Investigations
    Investigations
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    39
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac disorders
    left ventricle failure
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Nevous system disorders
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    anaemia
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    8
    Bone marrow oedema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eye disorders
    Eye Disorders
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    17
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    23
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    15
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    26
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2017
    The study timelines were extended, to have more time for recruitment. Additional saliva and blood samples were introduced.
    16 Apr 2020
    Sponsor Details updated Study timelines and total duration of study extended. Response assessment was clarified. Some responsibilities/contact data were updated.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36608320
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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