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    Clinical Trial Results:
    Multicentric phase II clinical trial to evaluate the activity of encorafenib and binimetinib before local treatment in patients with BRAF mutated melanoma with metastasis to the brain.

    Summary
    EudraCT number
    		 2018-002530-20
    Trial protocol
    		 ES  
    Global end of trial date
    31 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Apr 2025
    First version publication date
    24 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GEM-1802
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03898908
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español Multidisciplinar de Melanoma (GEM)
    Sponsor organisation address
    Velázquez, 7, 3ª planta, Madrid, Spain, 28001
    Public contact
    Technical Secretary, Grupo Español Multidisciplinar de Melanoma (GEM), secretaria@groupgem.es
    Scientific contact
    Technical Secretary, Grupo Español Multidisciplinar de Melanoma (GEM), secretaria@groupgem.es
    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
    31 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Intracranial objective response rate by RECIST 1.1 before local treatment
    Protection of trial subjects
    The study protocol already included measures to protect trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2019
    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
    Spain: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 the initial sample size was set at 48 patients, to ensure obtaining 38 evaluable patients. The cohort of symptomatic patients was exploratory and no formal sample calculation was performed, anticipating the inclusion of up to 15 patients. An interim analysis revealed no differences between cohorts. The trial was amended to analyze the full dataset.

    Pre-assignment
    Screening details
    		 Between July 2019 and October 2022, 48 patients were enrolled

    Period 1
    Period 1 title
    Overall study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Single arm study. No blinding applicable. No randomization.

    Arms
    Arm title
    		 COMBO450
    Arm description
    		 Encorafenib 450 mg daily orally and binimetinib 45 mg twice a day orally until progression of the disease, unacceptable toxicity or death. local radiation treatment started after start of treatment. Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg and 50 mg capsules

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg tablets

    Number of subjects in period 1
    		COMBO450
    Started
    48
    Completed
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study period
    Reporting group description
    		 -

    Reporting group values
    		 Overall study period Total
    Number of subjects
    		 48 48
    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
        median (full range (min-max))
    		 54 (18 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 24 24
    Eastern cooperative oncology group (ECOG) performance status (PS) at baseline
    Measure Description: The ECOG PS score describes a patient’s level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.). The score ranges from 0 (Fully active, able to carry on all pre-disease performance without restriction) to 5 (dead)
    Units: Subjects
        Score 0
    		 26 26
        Score 1
    		 20 20
        Score 2
    		 2 2
    Barthel Index
    Measure Description: Scale used to assess a patient's functional status and monitor their progress. The scale measures a person's ability to perform 10 basic activities of daily living, thereby providing a quantitative estimate of their degree of independence. Lower values indicate worse performance and more dependency.
    Units: Subjects
        Total dependent (0-4)
    		 3 3
        Severe dependent (5-12)
    		 4 4
        Moderate dependent (13-18)
    		 6 6
        Slight dependent (19-20)
    		 33 33
        Not applicable
    		 2 2
    BRAF genotype
    BRAF genotype refers to changes or mutations in the BRAF gene, which is located on chromosome 7. These changes may be linked to cancer.
    Units: Subjects
        V600E mutated
    		 41 41
        V600E not mutated
    		 7 7
    Brain symptoms
    Patients who experience symptoms related to the presence of brain metastasis, including (among others): Headaches. Seizures. Weakness in the arms or legs. Loss of balance. Memory loss. Speech disturbance/problems talking.
    Units: Subjects
        Asymptomatic
    		 25 25
        Symptomatic
    		 23 23
    Number of brain target lesion
    Units: Subjects
        1 intracranial lesion
    		 21 21
        2 intracranial lesions
    		 15 15
        3 or more intracranial lesions
    		 12 12
    Extracranial metastases
    Presence of extracranial disease.
    Units: Subjects
        Yes
    		 41 41
        No
    		 7 7
    Lactate dehydrogenase (LDH) levels
    LDH is determined in blood samples. this biomarker is indicative of inflammatory processes and in metastatic melanoma is considered a prognostic factor. Elevated levels of LDH are correlated with worse outcomes.
    Units: Subjects
        ≤ upper limit normal (ULN)
    		 26 26
        > ULN
    		 21 21
        Unknown
    		 1 1
    Corticosteroids use at baseline
    Number of patients having corticosteroids at baseline. Corticcosteroids are ofter prescribed to mitigate the symptoms of brain metastasis.
    Units: Subjects
        Yes
    		 33 33
        No
    		 15 15
    Previous anti- PD-1 based immunotherapy
    PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins. These treatments have an anticancer effect by promoting the activation of the immune system against tumor cells.
    Units: Subjects
        Anti PD-1
    		 11 11
        Anti PD-1 / anti CTLA-4
    		 5 5
        No previous PD-L1
    		 32 32
    Radiotherapy received in the E-BRAIN trial
    ype of radiation therapy scheduled during this trial. The radiotherapy type was chosen according to the principal investigator criteria and local standard procedures.
    Units: Subjects
        Radiosurgery (RS)
    		 10 10
        Fractioned stereotactic radiotherapy (FSRT)
    		 6 6
        Whole brain radiotherapy (WBRT)
    		 15 15
        None
    		 17 17
    Sum of longest diameters of intracranial target lesions
    This endpoint is a surrogate of the intracranial tumor burden. Here we show the sum of the longest diameter of intracranial metastasis
    Units: millimetre(s)
        median (full range (min-max))
    		 26.5 (6 to 134) -
    Corticosteroid dose
    The corticosteroids are collected as dexametasone equivalent. Here we report the daily dose prescribed. Measure Analysis Population Description: The dose of corticosteroids is only reported in patients receiving corticosteroids (N=33).
    Units: milligram(s)/24 hours
        median (full range (min-max))
    		 8 (1 to 16) -

    End points

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    End points reporting groups
    Reporting group title
    COMBO450
    Reporting group description
    		 Encorafenib 450 mg daily orally and binimetinib 45 mg twice a day orally until progression of the disease, unacceptable toxicity or death. local radiation treatment started after start of treatment. Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.

    Primary: Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset

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    End point title
    		 Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset [1]
    End point description
    iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.
    End point type
    Primary
    End point timeframe
    24 months after start of treatment
    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: This is a single arm study. No statistical comparison was planned. The results are indirectly compared with the current state of the art in the pathology.
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: Patients
        Patients with intracranial response
    34
        Patients with NO intracranial response
    13
        Not evaluable
    1
    No statistical analyses for this end point

    Primary: iORR by Modified RECIST 1.1 Before Local Radiotherapy Treatment in asymptomatic

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    End point title
    		 iORR by Modified RECIST 1.1 Before Local Radiotherapy Treatment in asymptomatic [2]
    End point description
    iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.
    End point type
    Primary
    End point timeframe
    24 months after start of treatment
    Notes
    [2] - 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: This is a single arm study. No statistical comparison was planned. The results are indirectly compared with the current state of the art in the pathology.
    End point values
    		 COMBO450
    Number of subjects analysed
    25 [3]
    Units: Patients
        Patients with intracranial response
    20
        Patients with NO intracranial response
    5
        Not evaluable
    0
    Notes
    [3] - Patients without symptoms of brain metastasis (Asymptomatic cohort)
    No statistical analyses for this end point

    Primary: iORR by Modified RECIST 1.1 Before Local Radiotherapy Treatment in symptomatic

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    End point title
    		 iORR by Modified RECIST 1.1 Before Local Radiotherapy Treatment in symptomatic [4]
    End point description
    iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.
    End point type
    Primary
    End point timeframe
    24 months after start of treatment
    Notes
    [4] - 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: This is a single arm study. No statistical comparison was planned. The results are indirectly compared with the current state of the art in the pathology.
    End point values
    		 COMBO450
    Number of subjects analysed
    23 [5]
    Units: Patients
        Patients with intracranial response
    14
        Patients with NO intracranial response
    8
        Not evaluable
    1
    Notes
    [5] - Patients with symptoms of brain metastasis (symptomatic)
    No statistical analyses for this end point

    Secondary: Duration of Intracranial Response

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    End point title
    		 Duration of Intracranial Response
    End point description
    Calculated as the time from the date of first documented CR or PR to the first documented intracranial progression or death due to underlying cancer accoridng to modified RECIST 1.1, in patients with documented intracranial CR or PR before local treatment.
    End point type
    Secondary
    End point timeframe
    Throughout the study period, up to approximately 24 months
    End point values
    		 COMBO450
    Number of subjects analysed
    34 [6]
    Units: month
        median (confidence interval 95%)
    5.6 (3.6 to 7.5)
    Notes
    [6] - Only patients with a response were analyzed
    No statistical analyses for this end point

    Secondary: Intracranial Progression-free Survival (iPFS) by RECIST 1.1

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    End point title
    		 Intracranial Progression-free Survival (iPFS) by RECIST 1.1
    End point description
    Defined as the time from the date of inclusion to the date of the first documented intracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (modified RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
    End point type
    Secondary
    End point timeframe
    Throughout the study period, up to approximately 24 months
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: month
        median (confidence interval 95%)
    8.5 (6.4 to 11.8)
    No statistical analyses for this end point

    Secondary: Extracranial Progression-free Survival (ePFS) in Both Cohorts

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    End point title
    		 Extracranial Progression-free Survival (ePFS) in Both Cohorts
    End point description
    Defined as the time from the date of inclusion to the date of the first documented extracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
    End point type
    Secondary
    End point timeframe
    Throughout the study period, up to approximately 24 months
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: month
        median (confidence interval 95%)
    7.7 (6.1 to 11.8)
    No statistical analyses for this end point

    Secondary: Intracranial Progression-free Rates

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    End point title
    		 Intracranial Progression-free Rates
    End point description
    Proportion of patients free of intracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
    End point type
    Secondary
    End point timeframe
    at 6 months (week 24), 12 months (week 48) and 24-month (week 96)
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: Percentage of patients
    number (confidence interval 95%)
        6 months
    66.8 (54.4 to 82.1)
        12 months
    29.5 (18.2 to 47.6)
        24 months
    5.5 (0.9 to 32)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Calculated as the time from date of inclusion to date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Throughout the study period, up to approximately 24 months
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: month
        median (confidence interval 95%)
    15.9 (10.7 to 21.4)
    No statistical analyses for this end point

    Secondary: Overall Survival Rates

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    End point title
    		 Overall Survival Rates
    End point description
    Proportion of of patients alive at 6 months, 12 month and 24-month considering date of inclusion estimated using Kaplan-Meier
    End point type
    Secondary
    End point timeframe
    at 6 months, 12 month and 24-month
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: Percentage of patients
    number (confidence interval 95%)
        6 months
    91.6 (84.1 to 99.8)
        12 months
    59.2 (46.2 to 76)
        24 months
    15.5 (6.7 to 35.8)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0

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    End point title
    		 Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
    End point description
    Number of patients experiencing treatment related adverse events. These events were graded accrding to CTCAE, a scale that ranges from 0 (less intense; no event) to 5 (death).
    End point type
    Secondary
    End point timeframe
    Throughout the study period, up to approximately 24 months
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: Patients
        Experienced Toxicity
    40
        Do NOT experienced toxicity
    8
    No statistical analyses for this end point

    Secondary: Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale

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    End point title
    		 Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale
    End point description
    The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 COMBO450
    Number of subjects analysed
    36 [7]
    Units: arbitrary units
    median (full range (min-max))
        Baseline
    78.4 (29.3 to 98.7)
        Week 8
    85.5 (48.6 to 99.4)
    Notes
    [7] - Patients with QoL completed
    No statistical analyses for this end point

    Secondary: Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale

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    End point title
    		 Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale
    End point description
    The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 COMBO450
    Number of subjects analysed
    26 [8]
    Units: Arbitrary units
    number (confidence interval 95%)
        Baseline
    78.4 (29.3 to 98.7)
        Week 24
    74.9 (47.3 to 97.9)
    Notes
    [8] - Patients who completed QoL questionnaires
    No statistical analyses for this end point

    Secondary: Extracranial Progression-free Rates

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    End point title
    		 Extracranial Progression-free Rates
    End point description
    Proportion of patients free of extracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
    End point type
    Secondary
    End point timeframe
    at 6 months (week 24), 12 months (week 48) and 24-month (week 96)
    End point values
    		 COMBO450
    Number of subjects analysed
    48
    Units: Percentage of patients
    number (confidence interval 95%)
        6 months
    64.1 (51.4 to 79.9)
        12 months
    31.2 (19.6 to 49.6)
        24 months
    5.8 (1 to 33.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period, up to approximately 24 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    COMBO450
    Reporting group description
    		 Encorafenib 450 mg daily orally and binimetinib 45 mg twice a day orally until progression of the disease, unacceptable toxicity or death. local radiation treatment started after start of treatment. Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.

    Serious adverse events
    		 COMBO450
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 48 (45.83%)
         number of deaths (all causes)
    33
         number of deaths resulting from adverse events
    0
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Brain metastasis surgery
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Epileptic status
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eplectic seizures
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Focal seizures
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Instability
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Movements involuntary
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Acute pain in rib zone irradiated to legs
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encorafenib overdose
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile syndrome of unknown origin
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left Hemiparesis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Clostridium Difficile infectious diarrhea
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Digestive bleeding
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Amigdalitis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary thromboembolism
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory sepsis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ight pleural empyema by streptococcus constellatus
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute renal insufficiency
         subjects affected / exposed
    1 / 48 (2.08%)
         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
    		 COMBO450
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 48 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 48 (18.75%)
         occurrences all number
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 48 (16.67%)
         occurrences all number
    8
    CPK increased
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Creatinine increased
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    GGT increased
         subjects affected / exposed
    8 / 48 (16.67%)
         occurrences all number
    8
    Other not specified
         subjects affected / exposed
    6 / 48 (12.50%)
         occurrences all number
    6
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    5 / 48 (10.42%)
         occurrences all number
    5
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    8 / 48 (16.67%)
         occurrences all number
    8
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 48 (10.42%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    12 / 48 (25.00%)
         occurrences all number
    12
    Fever
         subjects affected / exposed
    7 / 48 (14.58%)
         occurrences all number
    7
    Eye disorders
    Other not specified
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    5 / 48 (10.42%)
         occurrences all number
    5
    Diarrhea
         subjects affected / exposed
    13 / 48 (27.08%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    11 / 48 (22.92%)
         occurrences all number
    11
    Other not specified
         subjects affected / exposed
    4 / 48 (8.33%)
         occurrences all number
    4
    Vomiting
         subjects affected / exposed
    5 / 48 (10.42%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Other not specified
         subjects affected / exposed
    7 / 48 (14.58%)
         occurrences all number
    7
    Pruritus
         subjects affected / exposed
    3 / 48 (6.25%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 48 (8.33%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2019
    - Update of information regarding the treatment of toxicities associated with the investigational product encorafenib. - Update of safety aspects of the investigational product, encorafenib, following the update of information reflected in the investigator's manual version 11 of June 20, 2019 (new version 2.0 of the patient information sheet and informed consent form of August 29, 2019). - Change of the principal investigator of the study at the Virgen de la Macarena Hospital. Dr. Maria del Carmen Álamo de la Gala replaces Dr. Luis de la Cruz Merino.
    17 Jan 2020
    - Update of information regarding the discontinuation time of encorafenib + binimetinib during local treatment (radiotherapy). - Correction of an error regarding the specified dose for radiotherapy administration when using intensity-modulated radiotherapy (IMRT). - Correction of an error to standardize the test to be performed to detect possible pregnancies before and during participation in the trial in women of childbearing age. - Change of the study's principal investigator at the Clínica Universidad de Navarra. Dr. Miguel Fernández de Sanmamed Gutiérrez replaces Dr. Salvador Martín Algarra.
    03 Nov 2020
    - Change of IB, and update of information in the protocol and HIP-CI. - Update of the PI at the Canary Islands center. - The protocol changes refer to changes in inclusion criteria and data analysis.
    29 Mar 2021
    - A new participating center joins the study: ICO Hospitalet - A new principal investigator joins the study at ICO L'Hospitalet: Dr. Juan Martín Liberal
    29 Nov 2021
    Reduce the discontinuation of the trial treatment combination to 24 hours before and after the administration of local treatment. Modification of secondary objectives: the overall response objective is eliminated. Radiosurgery: For patients who do not meet criteria for radiosurgery (RS) or (SRS), the possibility of allowing certain cases is added after prior consultation with the trial coordinators, and specifically with the radiotherapy coordinator. Whole-cranial radiotherapy: The possibility of allowing hippocampal protection is added. The design titles of both cohort 1 and cohort 2 are modified (pages 27 and 28), specifying that patients who have received prior surgery can be included (instead of indicating prior local treatment). The definition of the asymptomatic cohort has been updated (page 29). Regulations have been made regarding inconsistencies detected. BUN has been eliminated. A paragraph has been added to clarify the protocol-required follow-up for patients who complete treatment due to treatment toxicity, according to inquiries received regarding this issue. Exclusion criterion 3 has been modified. The increase in the estimated recruitment period has been indicated.
    11 Nov 2022
    - Modification of the primary endpoint of the study: We request to study the intracranial objective response rate according to the modified RECIST 1.1 criteria before local treatment in cohort 1 and cohort 2. - This change is based on: - Various interim analyses (published in ESMO) have shown that the response rates of symptomatic and asymptomatic patients are similar, so it makes little sense to assess them separately as a primary endpoint. The joint analysis gives us greater statistical power (higher n). - At the level of clinical interest, it is more relevant to study both cohorts together, as has been recently reported in several clinical trials in this setting: TRICOTEL and COMBI-MB. - Incorporation of a new secondary endpoint: We request to incorporate the previous primary endpoint as a secondary endpoint: the intracranial objective response rate according to the modified RECIST 1.1 criteria before local treatment in cohort 1.

    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.
    Not applicable
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