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    Clinical Trial Results:
    A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY 86-9766) in combination with sorafenib as first line treatment in patients with RAS mutant Hepatocellular Carcinoma (HCC)

    Summary
    EudraCT number
    2013-000241-39
    Trial protocol
    AT   CZ   GB   DE   BE   IT   HU   ES  
    Global end of trial date
    08 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Feb 2018
    First version publication date
    10 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-9766 / 16728
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trialscontact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trialscontact@bayer.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
    08 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of refametinib in combination with sorafenib in subjects with Kirsten rat sarcoma viral oncogene homolog (KRAS/GTPase KRas) or Neuroblastoma RAS viral oncogene homolog (NRAS) mutant unresectable or metastatic Hepatocellular carcinoma (HCC).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Council of Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    19 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Japan: 2
    Worldwide total number of subjects
    16
    EEA total number of subjects
    9
    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
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study conducted in 21 countries (Austria, Belgium, China, Czech Republic, France, Germany, United Kingdom, Hong Kong, Hungary, Israel, Italy, Japan, New Zealand, Singapore, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey, United States) between 27 September 2013 (first subject first visit) and 08 February 2017 (last subject last visit).

    Pre-assignment
    Screening details
    In Stage 1 of the study, 820 subjects were included in screening phase 1 for KRAS or NRAS mutations, of them 24 completed screening phase 1 and enrolled for screening phase 2 (for study treatment eligibility). In phase 2 screening, 7 were screening failures and 1 died. Finally, 16 subjects were assigned to treatment. Stage 2 was not performed.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Refametinib 50 mg BID + Sorafenib 400 mg BID
    Arm description
    Subjects received refametinib 50 milligram (mg) as tablets (50 mg tablets or 20 mg + 30 mg tablets), orally, twice daily (bid) in combination with sorafenib 400 mg as tablets (2 * 200 mg tablets), orally bid without food in a 3-week treatment cycle until disease progression as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST), clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no hand-foot skin reaction (HFSR), fatigue, or gastrointestinal (GI) toxicities of grade 2 or higher occurred.
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sorafenib 400 mg as tablets (2 * 200 mg tablets), orally bid without food in a 3-week treatment cycle until disease progression as defined by mRECIST, clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no HFSR, fatigue, or GI toxicities of grade 2 or higher occurred.

    Investigational medicinal product name
    Refametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received refametinib 50 mg as tablets (50 mg tablets or 20 mg + 30 mg tablets), orally bid, without food in a 3-week treatment cycle until disease progression as defined by mRECIST, clinical progression, or any other criteria for discontinuation from study treatment were met.

    Number of subjects in period 1
    Refametinib 50 mg BID + Sorafenib 400 mg BID
    Started
    16
    Completed
    12
    Not completed
    4
         AE Not Associated With ClinicalDisease Progression
    2
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    16 16
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    67.2 ± 8.3 -
    Gender Categorical
    Units: Subjects
        Female
    4 4
        Male
    12 12
    Eastern cooperative oncology group (ECOG) Performance Status (PS)
    ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours (h), 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
    Units: Subjects
        Fully Active
    10 10
        Restricted Active
    6 6
    Macrovascular Invasion
    Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
    Units: Subjects
        No
    9 9
        Yes
    7 7
    Barcelona Clinic Liver Cancer (BCLC) stage
    BCLC classification divides HCC subjects in 5 stages (0=very early stage, A=early stage, B=intermediate stage, C=advanced stage and D=terminal stage) according to pre-established prognostic variables, and allocates therapies according to treatment-related status. Thus, it provides information on both prognostic prediction and treatment allocation.
    Units: Subjects
        A (Early Stage)
    2 2
        B (Intermediate Stage)
    2 2
        C (Advanced Stage)
    12 12

    End points

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    End points reporting groups
    Reporting group title
    Refametinib 50 mg BID + Sorafenib 400 mg BID
    Reporting group description
    Subjects received refametinib 50 milligram (mg) as tablets (50 mg tablets or 20 mg + 30 mg tablets), orally, twice daily (bid) in combination with sorafenib 400 mg as tablets (2 * 200 mg tablets), orally bid without food in a 3-week treatment cycle until disease progression as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST), clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no hand-foot skin reaction (HFSR), fatigue, or gastrointestinal (GI) toxicities of grade 2 or higher occurred.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (N=16) included all subjects assigned to the study treatment.

    Subject analysis set title
    Asia population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Asia population (N=6) included all Asian subjects who received refametinib 50 mg bid orally in combination with sorafenib 400 mg bid orally without food in a 3-week treatment cycle until disease progression as defined by mRECIST, clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no HFSR, fatigue, or GI toxicities of grade 2 or higher occurred.

    Subject analysis set title
    RoW population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    RoW population (N=10) included all RoW subjects who received refametinib 50 mg bid orally in combination with sorafenib 400 mg bid orally without food in a 3-week treatment cycle until disease progression as defined by mRECIST, clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no HFSR, fatigue, or GI toxicities of grade 2 or higher occurred.

    Primary: Objective Tumor Response Rate (ORR) According to mRECIST Assessed by Central Radiological Review

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    End point title
    Objective Tumor Response Rate (ORR) According to mRECIST Assessed by Central Radiological Review [1]
    End point description
    ORR was defined as the proportion of subjects who had a best response rating over the whole duration of the study of complete response (CR) or partial response (PR) according to mRECIST. CR was defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of less than (<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Subjects with no PR or CR, as well as subjects who prematurely discontinued without an evaluable assessment or subjects with an observed CR or PR that was not confirmed were considered non-responders for the analysis.
    End point type
    Primary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    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: As Stage 1 of the study was exploratory, there was no statistical testing at the end of Stage 1; all analyses were descriptive only.
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [2]
    10 [3]
    Units: Subjects
        Responder
    0
    0
        Non-Responder
    6
    10
    Notes
    [2] - FAS
    [3] - FAS
    No statistical analyses for this end point

    Secondary: ORR According to RECIST v.1.1 Assessed by Central Radiological Review

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    End point title
    ORR According to RECIST v.1.1 Assessed by Central Radiological Review
    End point description
    ORR was defined as the proportion of subjects who had a best response rating over the whole duration of the study of CR or PR according to RECIST v.1.1. CR was defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Subjects with no PR or CR, as well as subjects who prematurely discontinued without an evaluable assessment or subjects with an observed CR or PR that was not confirmed were considered non-responders for the analysis.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [4]
    10 [5]
    Units: Count of subjects
        Responder
    0
    0
        Non-Responder
    6
    10
    Notes
    [4] - FAS
    [5] - FAS
    No statistical analyses for this end point

    Secondary: ORR According to mRECIST and RECIST v.1.1 Assessed by Investigator

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    End point title
    ORR According to mRECIST and RECIST v.1.1 Assessed by Investigator
    End point description
    The investigator’s assessment of ORR according to mRECIST and RECIST 1.1 was defined as the proportion of subjects who have a best response rating over the whole duration of the study of CR or PR. CR was defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Subjects with no PR or CR, as well as subjects who prematurely discontinued without an evaluable assessment or subjects with an observed CR or PR that was not confirmed were considered non-responders for the analysis.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [6]
    10 [7]
    Units: Count of subjects
        Responder (mRECIST)
    0
    1
        Non-Responder (mRECIST)
    6
    9
        Responder (RECIST v.1.1)
    0
    1
        Non-Responder (RECIST v.1.1)
    6
    9
    Notes
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review

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    End point title
    Disease Control Rate (DCR) According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review
    End point description
    DCR was defined as the proportion of subjects who have a best response rating over the whole duration of the study of CR, PR or stable disease (SD) according to mRECIST and RECIST 1.1 criteria. CR was defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Subjects prematurely discontinuing without an assessment was considered non-responders for the analysis.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [8]
    10 [9]
    Units: Count of subjects
        Responder (mRECIST)
    2
    5
        Non-Responder (mRECIST)
    4
    5
        Responder (RECIST v.1.1)
    2
    5
        Non-Responder (RECIST v.1.1)
    4
    5
    Notes
    [8] - FAS
    [9] - FAS
    No statistical analyses for this end point

    Secondary: DCR According to mRECIST and RECIST v.1.1 Assessed by Investigator

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    End point title
    DCR According to mRECIST and RECIST v.1.1 Assessed by Investigator
    End point description
    DCR was defined as the proportion of subjects who have a best response rating over the whole duration of the study of CR, PR or stable disease (SD) according to mRECIST and RECIST 1.1 criteria. CR was defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Subjects prematurely discontinuing without an assessment was considered non-responders for the analysis.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [10]
    10 [11]
    Units: Count of subjects
        Responder (mRECIST)
    3
    4
        Non-Responder (mRECIST)
    3
    6
        Responder (RECIST v.1.1)
    3
    4
        Non-Responder (RECIST v.1.1)
    3
    6
    Notes
    [10] - FAS
    [11] - FAS
    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 time from the first day with study drug intake until death from any cause or until the last date the subject was known to be alive. In the below table, “99999” indicates that data was not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until death from any cause or until the last date the subject was known to be alive (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [12]
    10 [13]
    Units: Days
        median (confidence interval 95%)
    99 (39 to 99999)
    427 (36 to 99999)
    Notes
    [12] - FAS
    [13] - FAS
    No statistical analyses for this end point

    Secondary: Time to Radiographic Tumor Progression (TTRP) According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review

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    End point title
    Time to Radiographic Tumor Progression (TTRP) According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review
    End point description
    TTRP was defined as the time from the date of the first dose of study treatment (refametinib or sorafenib) to the date of the first observed radiographic disease progression. In the below table, “99999” indicates that data was not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [14]
    10 [15]
    Units: Days
    median (confidence interval 95%)
        mRECIST
    42 (39 to 99999)
    167 (42 to 99999)
        RECIST v.1.1
    42 (39 to 99999)
    126 (42 to 132)
    Notes
    [14] - FAS
    [15] - FAS
    No statistical analyses for this end point

    Secondary: TTRP According to mRECIST and RECIST v.1.1 Assessed by Investigator

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    End point title
    TTRP According to mRECIST and RECIST v.1.1 Assessed by Investigator
    End point description
    TTRP was defined as the time from the date of the first dose of study treatment (refametinib or sorafenib) to the date of the first observed radiographic disease progression.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [16]
    10 [17]
    Units: Days
    median (confidence interval 95%)
        mRECIST
    56 (28 to 84)
    84 (42 to 167)
        RECIST v.1.1
    56 (28 to 84)
    84 (42 to 167)
    Notes
    [16] - FAS
    [17] - FAS
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) According to mRECIST and RECIST v.1.1 Assessed by Investigator

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    End point title
    Duration of Response (DOR) According to mRECIST and RECIST v.1.1 Assessed by Investigator
    End point description
    DOR was defined as the time from the date of first objective radiological response to the date where PD was first documented radiologically or death (if death occurred first).
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6
    10
    Units: Days
        mRECIST
    0
    83
        RECIST v.1.1
    0
    83
    No statistical analyses for this end point

    Secondary: Time to Objective Response Assessed by Central Radiological Review and Investigator

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    End point title
    Time to Objective Response Assessed by Central Radiological Review and Investigator
    End point description
    Time to objective response was defined as the time from the date of the first dose of study treatment (refametinib or sorafenib) until the date when an objective tumor response (CR or PR) was first documented. CR was defined as disappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have decreased in size to have a short axis of <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Days
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [18] - No objective tumor responses were observed in this study.
    [19] - No objective tumor responses were observed in this study.
    No statistical analyses for this end point

    Secondary: Change in Tumor Size Assessed by Central Radiological Review and Investigator

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    End point title
    Change in Tumor Size Assessed by Central Radiological Review and Investigator
    End point description
    Number of participants with a determined best change in tumor size. Due to database constraints, best percent change in target lesions from baseline by mRECIST independent assessments(Reader 1 and Reader 2) and investigator assessments are displayed in the charts uploaded as attachment.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Refametinib 50 mg BID + Sorafenib 400 mg BID
    Number of subjects analysed
    16
    Units: Participants
        Reader 1
    13
        Reader 2
    12
        Investigator
    10
    Attachments
    Best percent change in target lessions by mRECIST
    No statistical analyses for this end point

    Secondary: Best Overall Response According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review

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    End point title
    Best Overall Response According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review
    End point description
    The overall best response was defined as the best response recorded from date of the first dose of study treatment (refametinib or sorafenib) until the end of treatment. In the below table, “99999” indicates that no overall response were observed.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [20]
    10 [21]
    Units: Percentage of subjectes
    number (confidence interval 95%)
        mRECIST - Unconfirmed PR
    16.7 (0.42 to 64.12)
    20.0 (2.52 to 55.61)
        mRECIST - SD
    16.7 (0.42 to 64.12)
    30.0 (6.67 to 65.25)
        mRECIST - PD
    50.0 (11.81 to 88.19)
    20.0 (2.52 to 55.61)
        mRECIST - Not Evaluable
    16.7 (0.42 to 64.12)
    99999 (99999 to 99999)
        mRECIST - Missing
    99999 (99999 to 99999)
    30.0 (6.67 to 65.25)
        RECIST v.1.1 - Unconfirmed PR
    16.7 (0.42 to 64.12)
    99999 (99999 to 99999)
        RECIST v.1.1 - SD
    16.7 (0.42 to 64.12)
    50.0 (18.71 to 81.29)
        RECIST v.1.1 - PD
    50.0 (11.81 to 88.19)
    20.0 (2.52 to 55.61)
        RECIST v.1.1 - Not Evaluable
    16.7 (0.42 to 64.12)
    99999 (99999 to 99999)
        RECIST v.1.1 - Missing
    99999 (99999 to 99999)
    30.0 (6.67 to 65.25)
    Notes
    [20] - FAS
    [21] - FAS
    No statistical analyses for this end point

    Secondary: Best Overall Response According to mRECIST and RECIST v.1.1 Assessed by Investigator

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    End point title
    Best Overall Response According to mRECIST and RECIST v.1.1 Assessed by Investigator
    End point description
    The overall best response was defined as the best response recorded from date of the first dose of study treatment (refametinib or sorafenib) until the end of treatment. In the below table, “99999” indicates that no overall response were observed.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [22]
    10 [23]
    Units: Percentage of subjects
    number (confidence interval 95%)
        mRECIST - PR
    99999 (99999 to 99999)
    10.0 (0.25 to 44.50)
        mRECIST - Unconfirmed PR
    16.7 (0.42 to 64.12)
    99999 (99999 to 99999)
        mRECIST - SD
    33.3 (4.33 to 77.72)
    30.0 (6.67 to 65.25)
        mRECIST - PD
    50.0 (11.81 to 88.19)
    30.0 (6.67 to 65.25)
        mRECIST – Missing
    99999 (99999 to 99999)
    30.0 (6.67 to 65.25)
        RECIST v.1.1 - PR
    99999 (99999 to 99999)
    10.0 (0.25 to 44.50)
        RECIST v.1.1 - Unconfirmed PR
    16.7 (0.42 to 64.12)
    99999 (99999 to 99999)
        RECIST v.1.1 - SD
    33.3 (4.33 to 77.72)
    30.0 (6.67 to 65.25)
        RECIST v.1.1 - PD
    50.0 (11.81 to 88.19)
    30.0 (6.67 to 65.25)
        RECIST v.1.1 - Missing
    99999 (99999 to 99999)
    30.0 (6.67 to 65.25)
    Notes
    [22] - FAS
    [23] - FAS
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review

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    End point title
    Progression-Free Survival (PFS) According to mRECIST and RECIST v.1.1 Assessed by Central Radiological Review
    End point description
    PFS was defined as the time from the date of the first dose of study treatment (refametinib or sorafenib) to the date of first observed disease progression (radiological or clinical, whichever was first) or death due to any cause, if death occurs before progression was documented. In the below table, “99999” indicates that data was not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [24]
    10 [25]
    Units: Days
    median (confidence interval 95%)
        mRECIST
    42 (39 to 99)
    84 (36 to 99999)
        RECIST v.1.1
    42 (39 to 99999)
    126 (36 to 132)
    Notes
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Secondary: PFS According to mRECIST and RECIST v.1.1 Assessed by Investigator

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    End point title
    PFS According to mRECIST and RECIST v.1.1 Assessed by Investigator
    End point description
    PFS was defined as the time from the date of the first dose of study treatment (refametinib or sorafenib) to the date of first observed disease progression (radiological or clinical, whichever was first) or death due to any cause, if death occurs before progression was documented. In the below table, “99999” indicates that data was not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until disease progression (evaluated in every 6 weeks) (total 41 months approximately)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [26]
    10 [27]
    Units: Days
    median (confidence interval 95%)
        mRECIST
    53 (14 to 84)
    65 (36 to 167)
        RECIST v.1.1
    53 (14 to 84)
    65 (36 to 167)
    Notes
    [26] - FAS
    [27] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in subject after providing written informed consent for participation in the study. AE may or may not be temporally or causally associated with the use of a medicinal product. A serious adverse event (SAE) was an AE resulting in any of following outcomes or deemed significant for any other reason: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly / birth defect; and another medical important serious event as judged by investigator. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 (+5) days after last administration of the study medication.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up 30 (+5) days after the last administration of study treatment; Subjects were contacted every 3 months to determine survival status, if applicable (approximately 3.5 years)
    End point values
    Asia population RoW population
    Number of subjects analysed
    6 [28]
    10 [29]
    Units: Count of subjects
        TEAE
    6
    10
        TESAE
    6
    7
    Notes
    [28] - SAF
    [29] - SAF
    No statistical analyses for this end point

    Other pre-specified: Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) at Stage 2

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    End point title
    Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) at Stage 2
    End point description
    The FACT-Hep (version 4) was a 45 item, self-administered, multi-dimensional, psychometrically sound questionnaire developed to measure the quality of life (QoL) in subjects with hepatobiliary cancers, including metastatic colorectal cancer, hepatocellular carcinoma (HCC), and pancreatic, gallbladder and bile duct cancer. The FACT-Generic (FACT-G) contains 27 core questionnaires designed to measure general aspects of HRQoL of subjects with any form of cancer. Hepatobiliary Cancer Subscale (HCS) contains 18 questionnaires, designed to measure specific concerns/problems related to QoL in subjects with hepatobiliary cancers. It contains 5 domains: Physical Well-Being (PWB), Social Well-Being (SWB), Emotional Well-Being (EWB), Functional Well- Being (FWB), and HCS. The FACT-Hep total score was the sum of PWB, SWB, EWB, FWB and HCS domain scores ranging from 0 to 180. Higher score means better HRQoL.
    End point type
    Other pre-specified
    End point timeframe
    Stage 2:On Day 1 of Cycle 1, 2, 3 and EOT (within 7 days after last drug administration)
    End point values
    Asia population RoW population
    Number of subjects analysed
    0 [30]
    0 [31]
    Units: Score on a scale
    Notes
    [30] - Data was not reported for this endpoint, since stage 2 analysis of the study was not performed.
    [31] - Data was not reported for this endpoint, since stage 2 analysis of the study was not performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring from start of study treatment up 30 (+5) days after the last administration of study treatment. Subjects were contacted every 3 months to determine survival status, if applicable (approximately 3.5 years)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Rest of world (RoW) population
    Reporting group description
    Rest of world (RoW) population: RoW subjects who received refametinib 50 mg bid orally in combination with sorafenib 400 mg bid orally without food in a 3-week treatment cycle until disease progression as defined by mRECIST, clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no HFSR, fatigue, or GI toxicities of grade 2 or higher occurred.

    Reporting group title
    Asia population
    Reporting group description
    Asia population: Asian subjects who received refametinib 50 mg bid orally in combination with sorafenib 400 mg bid orally without food in a 3-week treatment cycle until disease progression as defined by mRECIST, clinical progression, or any other criteria for discontinuation from study treatment were met. In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) was administered, which was escalated to the standard dose in Cycle 2, if no HFSR, fatigue, or GI toxicities of grade 2 or higher occurred.

    Serious adverse events
    Rest of world (RoW) population Asia population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    6 / 6 (100.00%)
         number of deaths (all causes)
    6
    3
         number of deaths resulting from adverse events
    2
    1
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 6 (66.67%)
         occurrences causally related to treatment / all
    2 / 6
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (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
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Rest of world (RoW) population Asia population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 10 (70.00%)
    6 / 6 (100.00%)
         occurrences all number
    18
    13
    Haematoma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Diabetic macroangiopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Fatigue
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 6 (66.67%)
         occurrences all number
    11
    4
    Gait disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    1
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    General physical health deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Confusional state
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Delirium
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Organic brain syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 6 (66.67%)
         occurrences all number
    13
    6
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 6 (50.00%)
         occurrences all number
    2
    9
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Lipase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    3
    Neutrophil count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    7
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    Weight increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Child-Pugh-Turcotte score increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    3
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Dysarthria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Sciatica
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Chorioretinopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Anal ulcer
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Ascites
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    2
    Constipation
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    7 / 10 (70.00%)
    3 / 6 (50.00%)
         occurrences all number
    15
    16
    Dyspepsia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    Toothache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Diabetic nephropathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 6 (66.67%)
         occurrences all number
    3
    8
    Hyperhidrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Eczema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Pain of skin
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    3
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    10
    1
    Nail ridging
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    Urticaria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Flank pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 6 (50.00%)
         occurrences all number
    4
    4
    Hypocalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    Hypophosphataemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    Hypoproteinaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    1
    Infections and infestations
    Dermatitis infected
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Candida infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Tinea versicolour
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2013
    1. Wording regarding use of refametinib tablets was clarified; -based on final pharmacokinetic results from a clinical relative bioavailability study (15221) where tablets exhibited comparable bioavailability to capsules, refametinib tablets could be used in clinical trials as an alternative for capsules. 2. Exclusion criteria were amended; -Subjects with a QTc greater than 480 milliseconds at the time of screening were excluded from the study due to the potential for QT prolongation with sorafenib -Exclusion criterion regarding women of childbearing potential was amended to reduce the time gap between the pregnancy evaluation and the beginning of treatment. -Exclusion criterion regarding systemic anticancer therapy was clarified, as subjects with prior systemic anticancer therapy were not eligible for this study. 3. A dose modification scheme for hepatotoxic events was included, since hepatotoxicity is an “identified risk” for the refametinib-sorafenib combination. 4. Guidance regarding reporting of contrast media was added. 5. Additional safety electrocardiograms (ECGs) were added in order to characterize the cardiovascular safety at anticipated maximum plasma concentrations of the study treatment.

    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.
    Occurrence of "±” in relation with geometric CV is auto-generated. Decimal places were automatically truncated if last decimal equals zero. Biomarker and PK anlysis were defined as additional objectives/variables of this study.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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