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    Clinical Trial Results:
    A multi-center, phase I/II study of BAY86-9766 in combination with gemcitabine in patients with locally advanced inoperable or metastatic pancreatic cancer

    Summary
    EudraCT number
    		 2010-019588-12
    Trial protocol
    		 DE   BE   GB   CZ   IT  
    Global end of trial date
    01 Aug 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Jul 2016
    First version publication date
    04 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Justfication needs revision

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-9766/14905
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01251640
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@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
    01 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I: •Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of BAY 86-9766 to be investigated in combination with the standard gemcitabine regimen in the subsequent Phase II part of this study Phase II •Determine the efficacy of the combination BAY 86-9766 / gemcitabine in terms of the overall response rate (confirmed complete response + partial response) according to response evaluation criteria in solid tumors (RECIST) Version 1.1
    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 Conference on Harmonization guideline E6: Good Clinical Practice. 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
    		 Gemcitabine was administered on Day 1 at a dose of 1000 milligram per meter square (mg/m^2) of body surface area intravenous (IV) infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 14
    Worldwide total number of subjects
    90
    EEA total number of subjects
    84
    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)
    52
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 22 study centers in 9 countries (8 countries in Europe, and the United States). The first patient’s first visit was on 01 January 2011 and the cut-off date for the final analysis was 01 August 2013, when last patient's last visit occurred.

    Pre-assignment
    Screening details
    		 Total of 121 subjects were screened, out of which 31 subjects failed screening. Ninety subjects were assigned to treatment. Subjects assigned to Phase 1 were reported separately from Phase 2. Ten evaluable subjects originally assigned to the 50 milligram (mg) arm of Phase 1 were subsequently reported also under the Phase 2 and so accounted for twic

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I
    Arm description
    		 Refametinib was administered orally on Day 2 at a dose of 30 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 milligram per meter square (mg/m^2) of body surface area intravenous (IV) infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks, thereafter, 3 out of 4 weeks. The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Investigational medicinal product name
    Refametinib
    Investigational medicinal product code
    BAY86-9766
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Refametinib was administered orally at a dose of 30 mg twice daily during the treatment cycle.

    Arm title
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Arm description
    		 Refametinib was administered orally on Day 2 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Refametinib
    Investigational medicinal product code
    BAY86-9766
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Refametinib was administered orally at a dose of 50 mg twice daily during the treatment cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks, thereafter, 3 out of 4 weeks. The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Arm title
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Arm description
    		 Refametinib was administered orally on Day 1 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Ten evaluable subjects originally assigned to the 50 mg arm of Phase I were subsequently reported also under the Phase II and so accounted for twice.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks, thereafter, 3 out of 4 weeks. The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Investigational medicinal product name
    Refametinib
    Investigational medicinal product code
    BAY86-9766
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Refametinib was administered orally at a dose of 50 mg twice daily during the treatment cycle.

    Number of subjects in period 1
    		Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Started
    10
    10
    80
    Treated
    10
    10
    80
    Survival follow up
    9
    9
    64
    Safety follow up
    10
    10
    74
    Terminated treatment
    10
    10
    80
    Completed
    0
    0
    0
    Not completed
    10
    10
    80
         Progressive disease – radiological progression
    5
    2
    26
         AE associated with clinical disease progression
    1
    -
    4
         Consent withdrawn by subject
    -
    1
    8
         Physician decision
    -
    -
    2
         Death
    -
    -
    6
         Switching to another therapy
    -
    -
    1
         AE unassociated with clinical disease progression
    3
    7
    31
         Progressive disease – clinical progression
    1
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Refametinib (BAY86-9766), 30 mg twice daily, Phase I
    Reporting group description
    		 Refametinib was administered orally on Day 2 at a dose of 30 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 milligram per meter square (mg/m^2) of body surface area intravenous (IV) infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Reporting group description
    		 Refametinib was administered orally on Day 2 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Reporting group description
    		 Refametinib was administered orally on Day 1 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Ten evaluable subjects originally assigned to the 50 mg arm of Phase I were subsequently reported also under the Phase II and so accounted for twice.

    Reporting group values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase II Total
    Number of subjects
    		 10 10 80 90
    Age categorical
    Units: Subjects
        Age 18 to less than or equal to 65 years
    		 5 5 50 52
        Age more than 65 years
    		 5 5 30 38
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.9 ( 13.9 ) 64.2 ( 8.8 ) 62.7 ( 9.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 36 40
        Male
    		 6 7 44 50
    Tumor node metastases (TNM) Classification at study entry
    TNM was based on size of tumor, if cancer cells had spread to nearby lymph nodes (LN), or distant (to other parts of the body) metastasis had occurred. Stages included: stage 0(no evidence of cancer cells), stage 1(T1N0M0), stage IIA(T0N1M0, T1N1M0, T2N0M0), stage IIB(T2N1M0, T3N0M0), stage III(any TN3M0), stage IV(anyT anyNM1), where T0=early form of tumor, T1= <2 centimeter(cm), T2=2-5 cm, T3= >2 cm, T4=large sized tumor, N0=not spread to LN, N1=spread to 1 to 3, N2=spread to 4 to 9, N3=spread >10 axillary LN, M0=no metastasis, M1= Metastasis.
    Units: Subjects
        Stage IIA
    		 0 0 1 1
        Stage IIB
    		 1 0 1 2
        Stage III
    		 1 2 10 11
        Stage IV
    		 8 8 68 76

    End points

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    End points reporting groups
    Reporting group title
    Refametinib (BAY86-9766), 30 mg twice daily, Phase I
    Reporting group description
    		 Refametinib was administered orally on Day 2 at a dose of 30 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 milligram per meter square (mg/m^2) of body surface area intravenous (IV) infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Reporting group description
    		 Refametinib was administered orally on Day 2 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Reporting group description
    		 Refametinib was administered orally on Day 1 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Ten evaluable subjects originally assigned to the 50 mg arm of Phase I were subsequently reported also under the Phase II and so accounted for twice.

    Subject analysis set title
    Safety analysis set (SAF) population: Phase I
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF population included all subjects who was assigned to study treatment with at least one intake of study drug.

    Subject analysis set title
    Maximum tolerated dose (MTD) population: Phase I
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MTD population included all SAF subjects fully evaluable for occurence of dose limiting toxicities (DLTs).

    Subject analysis set title
    Refametinib (BAY86-9766),dose escalation 30 mg, 50 mg, Phase I
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received refametinib 30 mg twice daily during the treatment cycle and 50 mg twice daily during the treatment cycle.

    Subject analysis set title
    Per protocol set (PPS) population: Phase II
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS population included all subjects who was assigned to treatment with no major protocol deviations for whom the primary efficacy variable was assessable.

    Primary: Number of Subjects With Dose Limiting Toxicities (DLT): Phase I

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    End point title
    		 Number of Subjects With Dose Limiting Toxicities (DLT): Phase I [1] [2]
    End point description
    DLT were defined using National Cancer Institute Common Toxicity Criteria (CTC) Adverse Event (NCI CTCAE) version4.0 as, Hematologic Toxicity: Grade 4 anemia, Grade 4 neutropenia lasting greater than (>) 10 days, Grade 3/4 neutropenia with fever >101 degree Fahrenheit , thrombocytopenia/Grade 3/4 thrombocytopenia with serious bleeding, or signs of serious bleeding and/or International Normalized Ratio >2.5 upper limit of normal (ULN) and/or partial thromboplastin time elevation of >2.5 ULN; Non-hematological toxicity: greater than or equal to (>=) Grade 3 toxicity, diarrhea only if refractory to maximal antidiarrheal therapy, skin toxicity Grade 3 for >2 weeks and Grade 4, missing >14 consecutive daily doses of BAY86-9766 due to drug-related toxicity, aspartate/alanine aminotransferase increase from Grade 1 to Grade 2-4, or from Grade 2 (in subjects with liver metastases) to Grade 3-4 in case of: 2nd occurrence after a 1st recovery to baseline level taking >14 days; or 3rd occurrence.
    End point type
    Primary
    End point timeframe
    From randomization up to the first 8 weeks of therapy
    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: All planned continuous and ordinal categorical variables were analyzed by descriptive statistics only.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    6 [3]
    6 [4]
    Units: subjects
        No
    5
    5
        Yes
    1
    1
    Notes
    [3] - MTD analysis set included all safety analysis set subjects fully evaluable for occurence of DLTs.
    [4] - MTD analysis set included all safety analysis set subjects fully evaluable for occurence of DLTs.
    No statistical analyses for this end point

    Primary: Tumor Response (Adjudicated Blinded Read Assessment): Phase II

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    End point title
    		 Tumor Response (Adjudicated Blinded Read Assessment): Phase II [5] [6]
    End point description
    Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response [Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)] observed during trial period assessed according to the RECIST v 1.1 criteria. The subject's best overall response assignment was depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. The blinded readers who were board certified, experienced and independent radiologists with broad expertise in oncology, radiology performed image evaluation independent from the conduct of the clinical part of the study.
    End point type
    Primary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [5] - 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: All planned continuous and ordinal categorical variables were analyzed by descriptive statistics only.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis was performed for each arm and reported under different endpoints. Hence not all the arms in the baseline period were reporting statistics in this endpoint.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [7]
    Units: percentage of subjects
    number (confidence interval 75%)
        Partial response
    23.3 (16.89 to 30.99)
        Stable disease
    38.3 (30.63 to 46.57)
        Unconfirmed Partial response
    11.7 (7 to 18.15)
        Progressive disease
    10 (5.69 to 16.23)
        Missing
    16.7 (11.12 to 23.76)
    Notes
    [7] - Primary analysis set (PAS) included the first 60 per protocol set (PPS) subjects.
    No statistical analyses for this end point

    Secondary: Tumor Response: Investigator Assessment: Phase I

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    End point title
    		 Tumor Response: Investigator Assessment: Phase I [8]
    End point description
    Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response [CR, PR, SD, or PD] observed during trial period assessed according to the RECIST v 1.1 criteria. The subject's best overall response assignment was depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. '99999' in the reported data indicates that there were no subjects with those responses.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis was performed for each arm and reported under different endpoints. Hence not all the arms in the baseline period were reporting statistics in this endpoint.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [9]
    10 [10]
    Units: percentage of subjects
    number (confidence interval 75%)
        Partial response
    20 (6.22 to 42.9)
    20 (6.22 to 42.9)
        Stable disease
    50 (28.45 to 71.55)
    40 (20.23 to 62.68)
        Unconfirmed Partial response
    20 (6.22 to 42.9)
    10 (1.33 to 31.67)
        Unconfirmed Stable disease
    10 (1.33 to 31.67)
    0 (0 to 0)
        Progressive disease
    0 (0 to 0)
    10 (1.33 to 31.67)
        Missing
    0 (0 to 0)
    20 (6.22 to 42.9)
    Notes
    [9] - Safety analysis set (SAF) included all subjects with at least one drug dose.
    [10] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Secondary: Disease Control (DC): Phase I

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    End point title
    		 Disease Control (DC): Phase I [11]
    End point description
    Disease control rate (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 SD according to RECIST (Version 1.1). SD had to be maintained for at least six weeks from the first demonstration of that rating. Confirmed DCR included unconfirmed CR or PR which is more than 6 weeks from the first dosing date and unconfirmed DCR included unconfirmed CR or PR which is less than 6 weeks from the first dosing date.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [12]
    10 [13]
    Units: percentage of subjects
    number (confidence interval 75%)
        Confirmed DCR
    90 (68.33 to 98.67)
    70 (46.85 to 87.25)
        Unconfirmed DCR
    10 (1.33 to 31.67)
    0 (0 to 0)
    Notes
    [12] - SAF included all subjects with at least one drug dose.
    [13] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Secondary: Disease Control (DC): Phase II

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    End point title
    		 Disease Control (DC): Phase II [14]
    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 SD according to RECIST (Version 1.1). SD had to be maintained for at least six weeks from the first demonstration of that rating. Confirmed DCR included unconfirmed CR or PR which is more than 6 weeks from the first dosing date and unconfirmed DCR included unconfirmed CR or PR which is less than 6 weeks from the first dosing date.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [15]
    Units: percentage of subjects
    number (confidence interval 75%)
        Confirmed DCR
    73.3 (65.47 to 80.13)
    Notes
    [15] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR): Phase I

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    End point title
    		 Duration of Response (DOR): Phase I [16]
    End point description
    DOR defined as the time from first observed tumor response (CR or PR) until disease progression or until death caused by disease progression. Only confirmed responses were considered. '99999' in the reported data indicates there were too few subjects in the data set, hence the data were not summarized.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [17]
    10 [18]
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [17] - SAF included all subjects with at least one drug dose.
    [18] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Secondary: Duration of Response: Phase II

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    End point title
    		 Duration of Response: Phase II [19]
    End point description
    DOR defined as the time from first observed tumor response (CR or PR) until disease progression or until death caused by disease progression. Only confirmed responses were considered.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    10 [20]
    Units: days
        median (confidence interval 95%)
    112 (84 to 265)
    Notes
    [20] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP): Phase I

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    End point title
    		 Time to Progression (TTP): Phase I [21]
    End point description
    TTP defined as the time from randomization (in this study randomization refers to the date of treatment assignment) to the first observation of progressive disease (PD, RECIST Version 1.1) or to the last date of a definite assessment (not status Unknown), if the subject was progression-free until that assessment. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [22]
    10 [23]
    Units: days
        median (confidence interval 95%)
    275 (107 to 392)
    168 (20 to 168)
    Notes
    [22] - SAF included all subjects with at least one drug dose.
    [23] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS): Phase I

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    End point title
    		 Progression-Free Survival (PFS): Phase I [24]
    End point description
    PFS defined as the time from randomization (Randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [25]
    10 [26]
    Units: days
        median (confidence interval 95%)
    163 (65 to 275)
    267 (20 to 322)
    Notes
    [25] - SAF included all subjects with at least one drug dose.
    [26] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP): Phase II

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    End point title
    		 Time to Progression (TTP): Phase II [27]
    End point description
    TTP defined as the time from randomization (in this study randomization referred to the date of treatment assignment) to the first observation of progressive disease (PD, RECIST Version 1.1) or to the last date of a definite assessment (not status Unknown), if the subject was progression-free until that assessment. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [28]
    Units: days
        median (confidence interval 95%)
    217 (140 to 278)
    Notes
    [28] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS): Phase II

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    End point title
    		 Progression-Free Survival (PFS): Phase II [29]
    End point description
    PFS defined as the time from randomization (Randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [30]
    Units: days
        median (confidence interval 95%)
    168 (115 to 225)
    Notes
    [30] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS): Phase I

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    End point title
    		 Overall Survival (OS): Phase I [31]
    End point description
    Overall survival defined as the time from randomization (in this study randomization referred to the date of treatment assignment) until death from any cause or until the last date the subject was known to be alive. Subjects who were still alive at the time of analysis were censored at their last date of last contact.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [32]
    10 [33]
    Units: days
        median (confidence interval 95%)
    355 (65 to 574)
    270 (140 to 553)
    Notes
    [32] - SAF included all subjects with at least one drug dose.
    [33] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS): Phase II

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    End point title
    		 Overall Survival (OS): Phase II [34]
    End point description
    Overall survival defined as the time from randomization (in this study randomization referred to the date of treatment assignment) until death from any cause or until the last date the subject was known to be alive. Subjects who were still alive at the time of analysis were censored at their last date of last contact.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [35]
    Units: days
        median (confidence interval 95%)
    270 (200 to 355)
    Notes
    [35] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Other pre-specified: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose: Phase I

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    End point title
    		 Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose: Phase I
    End point description
    MTD was determined by testing increasing doses up to 50 mg twice daily on dose escalation cohorts 1 to 2 with 3 subjects each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (= DLT in more than 30% of subjects). The MTD was the dose at which at most, one in six subjects in Cycle 1 had a DLT. RP2D was depended on the results of the Phase I part of this study.
    End point type
    Other pre-specified
    End point timeframe
    From start of the treatment upto the first eight weeks of therapy
    End point values
    		 Refametinib (BAY86-9766),dose escalation 30 mg, 50 mg, Phase I
    Number of subjects analysed
    12 [36]
    Units: milligram(s)
    number (not applicable)
        MTD
    50
        RP2D
    50
    Notes
    [36] - MTD analysis set included all safety analysis set subjects fully evaluable for occurence of DLTs.
    No statistical analyses for this end point

    Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Refametinib and Metabolite

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    End point title
    		 Maximum Observed Drug Concentration in Plasma (Cmax) of Refametinib and Metabolite [37]
    End point description
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    Cycle (C) 1 Day (D) 21 (C1D21), C1D22
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [38]
    10 [39]
    Units: microgram per liter
    geometric mean (geometric coefficient of variation)
        Refametinib: C1D21 (N= 8, 6)
    489 ( 66 )
    1046 ( 37 )
        Metabolite M-17: C1D21 (N= 8, 6)
    82.9 ( 31 )
    175 ( 75 )
        Refametinib: C1D22 (N= 8, 6)
    511 ( 79 )
    900 ( 67 )
        Metabolite M-17: C1D22 (N= 8, 6)
    100 ( 30 )
    164 ( 108 )
    Notes
    [38] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [39] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Gemcitabine and its Metabolite

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    End point title
    		 Maximum Observed Drug Concentration in Plasma (Cmax) of Gemcitabine and its Metabolite [40]
    End point description
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    C1D1, C1D22
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [41]
    10 [42]
    Units: milligram per liter
    geometric mean (geometric coefficient of variation)
        Gemcitabine: C1D1 (N=10, 10)
    2.49 ( 163 )
    2.74 ( 197 )
        Metabolite dFdU: C1D1 (N=10, 10)
    28 ( 22 )
    26.6 ( 25 )
        Gemcitabine: C1D22 (N=7, 5)
    6.06 ( 88 )
    3.5 ( 248 )
        Metabolite dFdU: C1D22 (N=7, 5)
    26.2 ( 19 )
    21.5 ( 46 )
    Notes
    [41] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [42] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Refametinib and Metabolite

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    End point title
    		 Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Refametinib and Metabolite [43]
    End point description
    Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    C1D21, C1D22
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [44]
    10 [45]
    Units: hours
    median (full range (min-max))
        Refametinib: C1D21 (N= 8, 6)
    3.5 (2 to 4)
    2 (1 to 4)
        Metabolite M-17: C1D21 (N= 8, 6)
    4 (2 to 4)
    2 (1 to 4)
        Refametinib: C1D22 (N= 8, 6)
    2.8 (2 to 4.5)
    1.8 (1 to 4.5)
        Metabolite M-17: C1D22 (N= 8, 6)
    2.5 (2 to 4.5)
    2 (1.6 to 8.5)
    Notes
    [44] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [45] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Gemcitabine and its Metabolite

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    End point title
    		 Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Gemcitabine and its Metabolite [46]
    End point description
    Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    C1D1, C1D22
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [47]
    10 [48]
    Units: hours
    median (full range (min-max))
        Gemcitabine: C1D1 (N=10, 10)
    0.8 (0.5 to 1)
    1 (0.4 to 1.5)
        Metabolite dFdU: C1D1 (N=10, 10)
    1 (0.5 to 2)
    1.2 (0.7 to 2.2)
        Gemcitabine: C1D22 (N=7, 5)
    1 (0.5 to 1)
    1 (0.5 to 1.2)
        Metabolite dFdU: C1D22 (N=7, 5)
    1 (1 to 2)
    1.2 (0.5 to 1.5)
    Notes
    [47] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [48] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Refametinib and Metabolite

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    End point title
    		 Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Refametinib and Metabolite [49]
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast) is defined as AUC from time zero to the last data point above the lower limit of quantification (2.00 microgram per liter). Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    C1D21, C1D22
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [50]
    10 [51]
    Units: microgram*hour per liter
    geometric mean (geometric coefficient of variation)
        Refametinib: C1D21 (N= 8, 6)
    2844 ( 80 )
    5186 ( 58 )
        Metabolite M-17: C1D21 (N= 8, 6)
    498 ( 28 )
    907 ( 68 )
        Refametinib: C1D22 (N= 8, 6)
    2979 ( 85 )
    4629 ( 65 )
        Metabolite M-17: C1D22 (N= 8, 6)
    595 ( 37 )
    850 ( 96 )
    Notes
    [50] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [51] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Gemcitabine and its Metabolite

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    End point title
    		 Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Gemcitabine and its Metabolite [52]
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast) is defined as AUC from time zero to the last data point above the lower limit of quantification (5.00 microgram per liter). Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    C1D1, C1D22
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [53]
    10 [54]
    Units: milligram*hour per liter
    geometric mean (geometric coefficient of variation)
        Gemcitabine: C1D1 (N=10, 10)
    2.4 ( 117 )
    2.39 ( 132 )
        Metabolite dFdU: C1D1 (N=10, 10)
    198 ( 38 )
    143 ( 26 )
        Gemcitabine: C1D22 (N=7, 5)
    4.93 ( 81 )
    2.83 ( 177 )
        Metabolite dFdU: C1D22 (N=7, 5)
    212 ( 45 )
    146 ( 41 )
    Notes
    [53] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [54] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Area Under the Curve From Time Zero to 8 hours [AUC (0 -8)] of Refametinib and Metabolite

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    End point title
    		 Area Under the Curve From Time Zero to 8 hours [AUC (0 -8)] of Refametinib and Metabolite [55]
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-8) is defined as area under the concentration from time zero to 8 hours. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.
    End point type
    Other pre-specified
    End point timeframe
    C1D21, C1D22
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [56]
    10 [57]
    Units: microgram*hour per liter
    geometric mean (geometric coefficient of variation)
        Refametinib: C1D21 (N= 8, 6)
    2857 ( 80 )
    5193 ( 58 )
        Metabolite M-17: C1D21 (N= 8, 6)
    499 ( 30 )
    909 ( 67 )
        Refametinib: C1D22 (N= 8, 6)
    2838 ( 85 )
    4457 ( 61 )
        Metabolite M-17: C1D22 (N= 8, 6)
    563 ( 31 )
    814 ( 87 )
    Notes
    [56] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [57] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Area under the Concentration-Time Curve (AUC) of Gemcitabine and its Metabolite

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    End point title
    		 Area under the Concentration-Time Curve (AUC) of Gemcitabine and its Metabolite [58]
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22. '99999' in the reported data indicates data for AUC was not calculated due to insufficient number of data points in the terminal phase.
    End point type
    Other pre-specified
    End point timeframe
    C1D1, C1D22
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [59]
    10 [60]
    Units: milligram*hour per liter
    geometric mean (geometric coefficient of variation)
        Gemcitabine: C1D1 (N=1, 0)
    99999 ( 99999 )
    99999 ( 99999 )
        Metabolite dFdU: C1D1 (N=0, 1)
    99999 ( 99999 )
    99999 ( 99999 )
        Gemcitabine: C1D22 (N=1, 2)
    99999 ( 99999 )
    9.344 ( 11.88 )
        Metabolite dFdU: C1D22 (N=0, 0)
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [59] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [60] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Refametinib and Metabolite

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    End point title
    		 Half Life Associated With Terminal Slope (t1/2) of Refametinib and Metabolite [61]
    End point description
    T1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours (h) and derived from the terminal slope of the concentration versus time curve. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22. '99999' in the reported data indicates data for t1/2 was not calculated due to insufficient number of data points in the terminal phase.
    End point type
    Other pre-specified
    End point timeframe
    C1D21, C1D22
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [62]
    10 [63]
    Units: hour
    geometric mean (geometric coefficient of variation)
        Refametinib: C1D21 (N= 8, 6)
    99999 ( 99999 )
    99999 ( 99999 )
        Metabolite M-17: C1D21 (N= 8, 6)
    99999 ( 99999 )
    99999 ( 99999 )
        Refametinib: C1D22 (N= 8, 6)
    99999 ( 99999 )
    99999 ( 99999 )
        Metabolite M-17: C1D22 (N= 8, 6)
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [62] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [63] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Gemcitabine and its Metabolite

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    End point title
    		 Half Life Associated With Terminal Slope (t1/2) of Gemcitabine and its Metabolite [64]
    End point description
    T1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours (h) and derived from the terminal slope of the concentration versus time curve. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22. '99999' in the reported data indicates data for t1/2 was not calculated due to insufficient number of data points in the terminal phase.
    End point type
    Other pre-specified
    End point timeframe
    C1D1, C1D22
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [65]
    10 [66]
    Units: hour
    geometric mean (geometric coefficient of variation)
        Gemcitabine: C1D1 (N=10, 10)
    99999 ( 99999 )
    99999 ( 99999 )
        Metabolite dFdU: C1D1 (N=10, 10)
    99999 ( 99999 )
    99999 ( 99999 )
        Gemcitabine: C1D22 (N=7, 5)
    99999 ( 99999 )
    99999 ( 99999 )
        Metabolite dFdU: C1D22 (N=7, 5)
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [65] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    [66] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase I

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    End point title
    		 Number of Subjects With Improvement or Deterioration in Worst Pain: Phase I [67]
    End point description
    A minimally important difference (MID) for the ‘worst’ pain item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), had been estimated as a 2-point change. The proportions of subjects who have improved [a decrease of greater than or equal to (>=) 2-points from baseline], remained stable (not reached a MID), deteriorated (an increase of >=2-points from baseline) scored by the ‘worst’ pain item were summarized at each time point.
    End point type
    Other pre-specified
    End point timeframe
    C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [68]
    10 [69]
    Units: subjects
        C1D29: Improved (N=7, 5)
    4
    2
        C1D29: Stable (N=7, 5)
    3
    3
        C1D29: Deteriorated (N=7, 5)
    0
    0
        C2D1: Improved (N=9, 6)
    4
    3
        C2D1: Stable (N=9, 6)
    5
    2
        C2D1: Deteriorated (N=9, 6)
    0
    1
        C3D1: Improved (N=5, 5)
    2
    3
        C3D1: Stable (N=5, 5)
    3
    1
        C3D1: Deteriorated (N=5, 5)
    0
    1
        C4D1: Improved (N=4, 3)
    2
    1
        C4D1: Stable (N=4, 3)
    2
    2
        C4D1: Deteriorated (N=4, 3)
    0
    0
        C5D1: Improved (N=4, 1)
    2
    0
        C5D1: Stable (N=4, 1)
    2
    1
        C5D1: Deteriorated (N=4, 1)
    0
    0
        C6D1: Improved (N=3, 1)
    2
    0
        C6D1: Stable (N=3, 1)
    0
    1
        C6D1: Deteriorated (N=3, 1)
    1
    0
        C7D1: Improved (N=4, 1)
    2
    0
        C7D1: Stable (N=4, 1)
    2
    0
        C7D1: Deteriorated (N=4, 1)
    0
    1
        C8D1: Improved (N=4, 0)
    2
    0
        C8D1: Stable (N=4, 0)
    2
    0
        C8D1: Deteriorated (N=4, 0)
    0
    0
        C9D1: Improved (N=4, 0)
    1
    0
        C9D1: Stable (N=4, 0)
    2
    0
        C9D1: Deteriorated (N=4, 0)
    1
    0
        C10D1: Improved (N=2, 0)
    0
    0
        C10D1: Stable (N=2, 0)
    2
    0
        C10D1: Deteriorated (N=2, 0)
    0
    0
        C11D1: Improved (N=2, 0)
    0
    0
        C11D1: Stable (N=2, 0)
    2
    0
        C11D1: Deteriorated (N=2, 0)
    0
    0
        C12D1: Improved (N=1, 0)
    0
    0
        C12D1: Stable (N= 1, 0)
    1
    0
        C12D1: Deteriorated (N=1, 0)
    0
    0
        C13D1: Improved (N=1, 0)
    0
    0
        C13D1: Stable (N=1, 0)
    1
    0
        C13D1: Deteriorated (N=1, 0)
    0
    0
        End of treatment visit: Improved (N=7, 7)
    2
    3
        End of treatment visit: Stable (N=7, 7)
    5
    4
        End of treatment visit: Deteriorated (N=7, 7)
    0
    0
    Notes
    [68] - SAF included all subjects with at least one drug dose.
    [69] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase II

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    End point title
    		 Number of Subjects With Improvement or Deterioration in Worst Pain: Phase II [70]
    End point description
    A MID for the ‘worst’ pain item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), had been estimated as a 2-point change. The proportions of subjects who have improved [a decrease of >= 2-points from baseline], remained stable (not reached a MID), deteriorated (an increase of >=2-points from baseline) scored by the ‘worst’ pain item were summarized at each time point.
    End point type
    Other pre-specified
    End point timeframe
    C2D1, C4D1, C6D1, C8D1, C10D1, C12D1, End of treatment visit
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [71]
    Units: subjects
        C2D1: Improved (N=34)
    16
        C2D1: Stable (N=34)
    12
        C2D1: Deteriorated (N=34)
    6
        C4D1: Improved (N=23)
    8
        C4D1: Stable (N=23)
    13
        C4D1: Deteriorated (N=23)
    2
        C6D1: Improved (N=14)
    4
        C6D1: Stable (N=14)
    8
        C6D1: Deteriorated (N=14)
    2
        C8D1: Improved (N=9)
    2
        C8D1: Stable (N=9)
    7
        C8D1: Deteriorated (N=9)
    0
        C10D1: Improved (N=4)
    1
        C10D1: Stable (N=4)
    3
        C10D1: Deteriorated (N=4)
    0
        C12D1: Improved (N=2)
    1
        C12D1: Stable (N=2)
    1
        C12D1: Deteriorated (N=2)
    0
        End of treatment visit: Improved (N=34)
    14
        End of treatment visit: Stable (N=34)
    15
        End of treatment visit: Deteriorated (N=34)
    5
    Notes
    [71] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Pain Response: Phase I

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    End point title
    		 Number of Subjects With Pain Response: Phase I [72]
    End point description
    Number of subjects with pain response were classified as yes, no or unknown. Pain response yes indicates decrease of at least 2 points from baseline in worst pain, an item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), and no increase in pain medication score; no indicates decrease less than 2 points from baseline in worst pain, or increase in pain medication score; and unknown indicates 1. decrease at least 2 points from baseline in worst pain, but the change in pain medication score is unknown and 2. no increase in pain medication score, but decrease from baseline in worst pain is unknown.
    End point type
    Other pre-specified
    End point timeframe
    C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit
    Notes
    [72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [73]
    10 [74]
    Units: subjects
        C1D29: No (N=9, 6)
    3
    3
        C1D29: Yes (N=9, 6)
    4
    1
        C1D29: Unknown (N=9, 6)
    2
    2
        C2D1: No (N=9, 6)
    6
    3
        C2D1: Yes (N=9, 6)
    2
    2
        C2D1: Unknown (N=9, 6)
    1
    1
        C3D1: No (N=5, 5)
    3
    2
        C3D1: Yes (N=5, 5)
    1
    2
        C3D1: Unknown (N=5, 5)
    1
    1
        C4D1: No (N=4, 3)
    2
    2
        C4D1: Yes (N=4, 3)
    2
    0
        C4D1: Unknown (N=4, 3)
    0
    1
        C5D1: No (N=4, 1)
    2
    1
        C5D1: Yes (N=4, 1)
    2
    0
        C5D1: Unknown (N=4, 1)
    0
    0
        C6D1: No (N=4, 1)
    1
    1
        C6D1: Yes (N=4, 1)
    2
    0
        C6D1: Unknown (N=4, 1)
    1
    0
        C7D1: No (N=4, 1)
    2
    1
        C7D1: Yes (N=4, 1)
    2
    0
        C7D1: Unknown (N=4, 1)
    0
    0
        C8D1: No (N=4, 0)
    2
    0
        C8D1: Yes (N=4, 0)
    1
    0
        C8D1: Unknown (N=4, 0)
    1
    0
        C9D1: No (N=4, 0)
    3
    0
        C9D1: Yes (N=4, 0)
    1
    0
        C9D1: Unknown (N=4, 0)
    0
    0
        C10D1: No (N=2, 0)
    2
    0
        C10D1: Yes (N=2, 0)
    0
    0
        C10D1: Unknown (N=2, 0)
    0
    0
        C11D1: No (N=2, 0)
    2
    0
        C11D1: Yes (N=2, 0)
    0
    0
        C11D1: Unknown (N=2, 0)
    0
    0
        C12D1: No (N=1, 0)
    1
    0
        C12D1: Yes (N=1, 0)
    0
    0
        C12D1: Unknown (N=1, 0)
    0
    0
        C13D1: No (N=1, 0)
    1
    0
        C13D1: Yes (N=1, 0)
    0
    0
        C13D1: Unknown (N=1, 0)
    0
    0
        End of treatment visit: No (N=7, 8)
    6
    4
        End of treatment visit: Yes (N=7, 8)
    1
    2
        End of treatment visit: Unknown (N=7, 8)
    0
    2
    Notes
    [73] - SAF included all subjects with at least one drug dose.
    [74] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Pain Response: Phase II

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    End point title
    		 Number of Subjects With Pain Response: Phase II [75]
    End point description
    Number of subjects with pain response were classified as yes, no or unknown. Pain response yes indicates decrease of at least 2 points from baseline in worst pain, an item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), and no increase in pain medication score; no indicates decrease less than 2 points from baseline in worst pain, or increase in pain medication score; and unknown indicates 1. decrease at least 2 points from baseline in worst pain, but the change in pain medication score is unknown and 2. no increase in pain medication score, but decrease from baseline in worst pain is unknown.
    End point type
    Other pre-specified
    End point timeframe
    C2D1, C4D1, C6D1, C8D1, C10D1, C12D1, End of treatment visit
    Notes
    [75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [76]
    Units: subjects
        C2D1: No (N=34)
    18
        C2D1: Yes (N=34)
    10
        C2D1: Unknown (N=34)
    8
        C4D1: No (N=25)
    16
        C4D1: Yes (N=25)
    4
        C4D1: Unknown (N=25)
    5
        C6D1: No (N=15)
    10
        C6D1: Yes (N=15)
    2
        C6D1: Unknown (N=15)
    3
        C8D1: No (N=10)
    7
        C8D1: Yes (N=10)
    2
        C8D1: Unknown (N=10)
    1
        C10D1: No (N=5)
    3
        C10D1: Yes (N=5)
    1
        C10D1: Unknown (N=5)
    1
        C12D1: No (N=3)
    1
        C12D1: Yes (N=3)
    1
        C12D1: Unknown (N=3)
    1
        End of treatment visit: No (N=37)
    20
        End of treatment visit: Yes (N=37)
    8
        End of treatment visit: Unknown (N=37)
    9
    Notes
    [76] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase I

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    End point title
    		 Brief Pain Inventory – Short Form (BPI-SF) score: Phase I [77]
    End point description
    Patient Reported Outcomes (PROs) data, as measured by the BPI-SF and the pain medication diary. BPI-SF was a 15-item, self administered, clinically valid, reliable and responsive measure developed to assess pain related to cancer. The instrument was available in validated multilingual versions; on average, it requires less than 10 minutes to complete the questionnaire. BPI-SF is typically scored by averaging the pain severity score and overall pain interference score. Scores range from 0-10 and a higher score indicates a higher level of pain/interference. Data presented for BPI-SF as total score, pain severity score, pain interference score (PIS) and for the average of general activity, walking, and work [activity-related dimension], and of relations, mood, and enjoyment [mood-related dimension] at each assessment time point. '99999' in the reported data indicates that there were no subjects evaluated at the specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment (EOT) visit
    Notes
    [77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [78]
    10 [79]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline: Pain severity score (N=10, 9)
    2.95 ( 2.54 )
    2 ( 2.05 )
        C1D29: Pain severity score (N=7, 6)
    0.79 ( 0.81 )
    0.42 ( 0.68 )
        C2D1: Pain severity score (N=9, 6)
    1.31 ( 2.2 )
    1.04 ( 1.37 )
        C3D1: Pain severity score (N=5, 5)
    0.25 ( 0.43 )
    1.25 ( 1.21 )
        C4D1: Pain severity score (N=4, 3)
    0.25 ( 0.5 )
    0.33 ( 0.58 )
        C5D1: Pain severity score (N=4, 1)
    0.5 ( 1 )
    0 ( 99999 )
        C6D1: Pain severity score (N=3, 1)
    1 ( 1.73 )
    0 ( 99999 )
        C7D1: Pain severity score (N=4, 1)
    0.5 ( 1 )
    4.5 ( 99999 )
        C8D1: Pain severity score (N=4, 0)
    0.56 ( 1.13 )
    99999 ( 99999 )
        C9D1: Pain severity score (N=4, 0)
    1.13 ( 1.79 )
    99999 ( 99999 )
        C10D1: Pain severity score (N=2, 0)
    1 ( 1.41 )
    99999 ( 99999 )
        C11D1: Pain severity score (N=2, 0)
    0.75 ( 1.06 )
    99999 ( 99999 )
        C12D1: Pain severity score (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        C13D1: Pain severity score (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        End of treatment: Pain severity score (N=7, 8)
    0.93 ( 0.85 )
    1.16 ( 1.28 )
        Baseline: PIS (N=10, 9)
    2.7 ( 2.59 )
    1.98 ( 2.54 )
        C1D29: PIS (N=7, 6)
    1.41 ( 2.18 )
    0.48 ( 0.79 )
        C2D1: PIS (N=9, 6)
    1.41 ( 2.47 )
    1.52 ( 1.8 )
        C3D1: PIS (N=5, 5)
    0.4 ( 0.82 )
    1.91 ( 2.22 )
        C4D1: PIS (N=4, 3)
    0.64 ( 1.29 )
    2.05 ( 3.55 )
        C5D1: PIS (N=4, 1)
    0.57 ( 1.14 )
    0 ( 99999 )
        C6D1: PIS (N=3, 1)
    0.95 ( 1.65 )
    0 ( 99999 )
        C7D1: PIS (N=4, 1)
    0.57 ( 1.14 )
    5.57 ( 99999 )
        C8D1: PIS (N=4, 0)
    0.57 ( 1.14 )
    99999 ( 99999 )
        C9D1: PIS (N=4, 0)
    1.11 ( 1.69 )
    99999 ( 99999 )
        C10D1: PIS (N=2, 0)
    0.5 ( 0.71 )
    99999 ( 99999 )
        C11D1: PIS (N=2, 0)
    0.64 ( 0.91 )
    99999 ( 99999 )
        C12D1: PIS (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        C13D1: PIS (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        End of treatment visit: PIS (N=7, 8)
    1.53 ( 2.37 )
    1.86 ( 2.19 )
        Baseline: PIS-activity-related dimension (N=10, 9)
    2.73 ( 2.96 )
    1.96 ( 2.66 )
        C1D29: PIS-activity-related dimension (N=7, 6)
    1.67 ( 2.86 )
    0.33 ( 0.52 )
        C2D1: PIS-activity-related dimension (N=9, 6)
    1.37 ( 2.37 )
    1.44 ( 1.71 )
        C3D1: PIS-activity-related dimension (N=5, 5)
    0.47 ( 0.87 )
    1.93 ( 2.28 )
        C4D1: PIS-activity-related dimension (N=4, 3)
    0.5 ( 1 )
    1.33 ( 2.31 )
        C5D1: PIS-activity-related dimension (N=4, 1)
    0.58 ( 1.17 )
    0 ( 99999 )
        C6D1: PIS-activity-related dimension (N=3, 1)
    1 ( 1.73 )
    0 ( 99999 )
        C7D1: PIS-activity-related dimension (N=4, 1)
    0.58 ( 1.17 )
    7 ( 99999 )
        C8D1: PIS-activity-related dimension (N=4, 0)
    0.5 ( 1 )
    99999 ( 99999 )
        C9D1: PIS-activity-related dimension (N=4, 0)
    1.08 ( 1.57 )
    99999 ( 99999 )
        C10D1: PIS-activity-related dimension (N=2, 0)
    0.67 ( 0.94 )
    99999 ( 99999 )
        C11D1: PIS-activity-related dimension (N=2, 0)
    0.83 ( 1.18 )
    99999 ( 99999 )
        C12D1: PIS-activity-related dimension (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        C13D1: PIS-activity-related dimension (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        EOT: PIS-activity-related dimension (N=7, 8)
    1.67 ( 2.51 )
    1.58 ( 1.68 )
        Baseline: PIS-mood-related dimension (N=10, 9)
    2.33 ( 2.87 )
    1.93 ( 2.42 )
        C1D29: PIS-mood-related dimension (N=7, 6)
    1.38 ( 2.14 )
    0.61 ( 1.2 )
        C2D1: PIS-mood-related dimension (9, 6)
    1.56 ( 2.82 )
    1.89 ( 2.25 )
        C3D1: PIS-mood-related dimension (N=5, 5)
    0.33 ( 0.75 )
    1.87 ( 2.22 )
        C4D1: PIS-mood-related dimension (N=4, 3)
    0.67 ( 1.33 )
    2.67 ( 4.62 )
        C5D1: PIS-mood-related dimension (N=4, 1)
    0.5 ( 1 )
    0 ( 99999 )
        C6D1: PIS-mood-related dimension (N=3, 1)
    0.89 ( 1.54 )
    0 ( 99999 )
        C7D1: PIS-mood-related dimension (N=4, 1)
    0.5 ( 1 )
    5.67 ( 99999 )
        C8D1: PIS-mood-related dimension (N=4, 0)
    0.5 ( 1 )
    99999 ( 99999 )
        C9D1: PIS-mood-related dimension (N=4, 0)
    1.17 ( 1.91 )
    99999 ( 99999 )
        C10D1: PIS-mood-related dimension (N=2, 0)
    0.33 ( 0.47 )
    99999 ( 99999 )
        C11D1: PIS-mood-related dimension (N=2, 0)
    0.67 ( 0.94 )
    99999 ( 99999 )
        C12D1: PIS-mood-related dimension (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        C13D1: PIS-mood-related dimension (N=1, 0)
    0 ( 99999 )
    99999 ( 99999 )
        EOT: PIS-mood-related dimension (N=7, 8)
    1.67 ( 2.87 )
    2.04 ( 2.69 )
    Notes
    [78] - SAF included all subjects with at least one drug dose.
    [79] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase II

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    End point title
    		 Brief Pain Inventory – Short Form (BPI-SF) score: Phase II [80]
    End point description
    PROs data, as measured by the BPI-SF and the pain medication diary. BPI-SF was a 15-item, self administered, clinically valid, reliable and responsive measure developed to assess pain related to cancer. The instrument was available in validated multilingual versions; on average, it requires less than 10 minutes to complete the questionnaire. BPI-SF is typically scored by averaging the pain severity score and overall pain interference score. Scores range from 0-10 and a higher score indicates a higher level of pain/interference. Data presented for BPI-SF as total score, pain severity score, PIS and for the average of general activity, walking, and work [activity-related dimension], and of relations, mood, and enjoyment [mood-related dimension] at each assessment time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline,C1D1, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D9, C10D1, C11D1, C12D1, C13D1, End of treatment visit
    Notes
    [80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [81]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline: Pain severity score (N=54)
    1.64 ( 1.67 )
        C1D1: Pain severity score (N=1)
    3.5 ( 99999 )
        C1D29: Pain severity score (N=39)
    1.28 ( 1.66 )
        C2D1: Pain severity score (N=36)
    0.97 ( 1.63 )
        C3D1: Pain severity score (N=30)
    0.94 ( 1.51 )
        C4D1: Pain severity score (N=23)
    0.73 ( 1.39 )
        C5D1: Pain severity score (N=23)
    0.86 ( 1.78 )
        C6D1: Pain severity score (N=15)
    1.02 ( 2.52 )
        C7D1: Pain severity score (N=12)
    0.58 ( 1.32 )
        C8D1: Pain severity score (N=10)
    0.1 ( 0.32 )
        C9D1: Pain severity score (N=9)
    0.42 ( 0.64 )
        C10D1: Pain severity score (N=5)
    0.05 ( 0.11 )
        C11D1: Pain severity score (N=3)
    0 ( 0 )
        C12D1: Pain severity score (N=3)
    0.17 ( 0.29 )
        C13D1: Pain severity score (N=1)
    0 ( 99999 )
        End of treatment: Pain severity score (N=37)
    1.36 ( 2 )
        Baseline: PIS (N=53)
    1.62 ( 2.1 )
        C1D1: PIS (N=1)
    4.86 ( 99999 )
        C1D29: PIS (N=39)
    1.27 ( 2.17 )
        C2D1: PIS (N=36)
    1.22 ( 2.05 )
        C3D1: PIS (N=29)
    1.4 ( 1.91 )
        C4D1: PIS (N=24)
    1.08 ( 1.99 )
        C5D1: PIS (N=23)
    0.84 ( 1.96 )
        C6D1: PIS (N=15)
    0.93 ( 2.32 )
        C7D1: PIS (N=12)
    0.71 ( 1.62 )
        C8D1: PIS (N=10)
    0.34 ( 0.56 )
        C9D1: PIS (N=9)
    0.33 ( 0.6 )
        C10D1: PIS (N=5)
    0.06 ( 0.13 )
        C11D1: PIS (N=3)
    0 ( 0 )
        C12D1: PIS (N=3)
    0.1 ( 0.16 )
        C13D1: PIS (N=1)
    0 ( 99999 )
        End of treatment visit: PIS (N=37)
    2.01 ( 2.76 )
        Baseline: PIS-activity-related dimension (N=52)
    1.49 ( 2.32 )
        C1D1: PIS-activity-related dimension (N=1)
    5 ( 99999 )
        C1D29: PIS-activity-related dimension (N=39)
    1.22 ( 2.19 )
        C2D1: PIS-activity-related dimension (N=36)
    1.2 ( 2.03 )
        C3D1: PIS-activity-related dimension (N=29)
    1.41 ( 2.09 )
        C4D1: PIS-activity-related dimension (N=24)
    1.07 ( 2.07 )
        C5D1: PIS-activity-related dimension (N=23)
    0.8 ( 2.01 )
        C6D1: PIS-activity-related dimension (N=15)
    0.96 ( 2.52 )
        C7D1: PIS-activity-related dimension (N=12)
    1.08 ( 2.21 )
        C8D1: PIS-activity-related dimension (N=10)
    0.47 ( 0.79 )
        C9D1: PIS-activity-related dimension (N=8)
    0.33 ( 0.71 )
        C10D1: PIS-activity-related dimension (N=5)
    0 ( 0 )
        C11D1: PIS-activity-related dimension (N=3)
    0 ( 0 )
        C12D1: PIS-activity-related dimension (N=3)
    0.22 ( 0.38 )
        C13D1: PIS-activity-related dimension (N=1)
    0 ( 99999 )
        EOT: PIS-activity-related dimension (N=37)
    2.09 ( 2.86 )
        Baseline: PIS-mood-related dimension (N=51)
    1.5 ( 2.01 )
        C1D1: PIS-mood-related dimension (N=1)
    5.67 ( 99999 )
        C1D29: PIS-mood-related dimension (N=39)
    1.23 ( 2.26 )
        C2D1: PIS-mood-related dimension (N=35)
    1.19 ( 2.01 )
        C3D1: PIS-mood-related dimension (N=29)
    1.46 ( 1.95 )
        C4D1: PIS-mood-related dimension (N=24)
    1.17 ( 2.33 )
        C5D1: PIS-mood-related dimension (N=23)
    0.91 ( 2.08 )
        C6D1: PIS-mood-related dimension (N=15)
    0.87 ( 2.03 )
        C7D1: PIS-mood-related dimension (N=12)
    0.53 ( 1.63 )
        C8D1: PIS-mood-related dimension (N=10)
    0.3 ( 0.51 )
        C9D1: PIS-mood-related dimension (N=9)
    0.3 ( 0.51 )
        C10D1: PIS-mood-related dimension (N=5)
    0.07 ( 0.15 )
        C11D1: PIS-mood-related dimension (N=3)
    0 ( 0 )
        C12D1: PIS-mood-related dimension (N=3)
    0 ( 0 )
        C13D1: PIS-mood-related dimension (N=1)
    0 ( 99999 )
        EOT: PIS-mood-related dimension (N=37)
    1.92 ( 2.72 )
    Notes
    [81] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase I

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    End point title
    		 Number of Subjects Recorded Pain Medication in Diary: Phase I [82]
    End point description
    Pain is directly associated with the use of analgesics. Therefore, a diary was also completed by the subjects to ensure all key information (that is, type of pain medication, dosage and frequency) related to the use of analgesics commonly used to control pain in pancreatic cancer was fully captured. Subjects were to record all pain medications taken during the last 48 hours, only, prior to their scheduled visit at the study site.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit
    Notes
    [82] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Number of subjects analysed
    10 [83]
    10 [84]
    Units: subjects
        Baseline: No (N=10, 9)
    0
    0
        Baseline: Yes (N=10, 9)
    10
    9
        C1D29: No (N=9, 5)
    3
    0
        C1D29: Yes (N=9, 5)
    6
    5
        C2D1: No (N=9, 6)
    1
    0
        C2D1: Yes (N=9, 6)
    8
    6
        C3D1: No (N=5, 5)
    0
    1
        C3D1: Yes (N=5, 5)
    5
    4
        C4D1: No (N =4, 3)
    0
    0
        C4D1: Yes (N=4, 3)
    4
    3
        C5D1: No (N=4, 1)
    0
    0
        C5D1: Yes (N=4, 1)
    4
    1
        C6D1: No (N=4, 0)
    0
    0
        C6D1: Yes (N=4, 0)
    4
    0
        C7D1: No (N=4, 1)
    0
    0
        C7D1: Yes (N=4, 1)
    4
    1
        C8D1: No (N=4, 0)
    0
    0
        C8D1: Yes (N=4, 0)
    4
    0
        C9D1: No (N=4, 0)
    0
    0
        C9D1: Yes (N=4, 0)
    4
    0
        C10D1: No (N=2, 0)
    0
    0
        C10D1: Yes (N=2, 0)
    2
    0
        C11D1: No (N=2, 0)
    0
    0
        C11D1: Yes (N=2, 0)
    2
    0
        C12D1: No (N=1, 0)
    0
    0
        C12D1: Yes (N=1, 0)
    1
    0
        C13D1: No (N=1, 0)
    0
    0
        C13D1: Yes (N=1, 0)
    1
    0
        End of treatment visit: No (N=7, 8)
    2
    0
        End of treatment visit: Yes (N=7, 8)
    5
    8
    Notes
    [83] - SAF included all subjects with at least one drug dose.
    [84] - SAF included all subjects with at least one drug dose.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase II

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    End point title
    		 Number of Subjects Recorded Pain Medication in Diary: Phase II [85]
    End point description
    Pain is directly associated with the use of analgesics. Therefore, a diary was also completed by the subjects to ensure all key information (that is, type of pain medication, dosage and frequency) related to the use of analgesics commonly used to control pain in pancreatic cancer was fully captured. Subjects were to record all pain medications taken during the last 48 hours, only, prior to their scheduled visit at the study site.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit
    Notes
    [85] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.
    End point values
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    60 [86]
    Units: subjects
        Baseline: No (N=57)
    8
        Baseline: Yes (N=57)
    49
        C1D29: No (N=43)
    10
        C1D29: Yes (N=43)
    33
        C2D1: No (N=35)
    5
        C2D1: Yes (N=35)
    30
        C3D1: No (N=29)
    5
        C3D1: Yes (N=29)
    24
        C4D1: No (N=24)
    3
        C4D1: Yes (N=24)
    21
        C5D1: No (N=23)
    2
        C5D1: Yes (N=23)
    21
        C6D1: No (N=14)
    2
        C6D1: Yes (N=14)
    12
        C7D1: No (N=14)
    2
        C7D1: Yes (N=14)
    12
        C8D1: No (N=11)
    2
        C8D1: Yes (N=11)
    9
        C9D1: No (N=9)
    2
        C9D1: Yes (N=9)
    7
        C10D1: No (N=4)
    0
        C10D1: Yes (N=4)
    4
        C11D1: No (N=3)
    0
        C11D1: Yes (N=3)
    3
        C12D1: No (N=3)
    0
        C12D1: Yes (N=3)
    3
        C13D1: No (N=1)
    0
        C13D1: Yes (N=1)
    1
        End of treatment visit: No (N=35)
    6
        End of treatment visit: Yes (N=35)
    29
    Notes
    [86] - PAS included the first 60 PPS subjects.
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with KRAS Mutational Status

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    End point title
    		 Number of subjects with KRAS Mutational Status
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    0 [87]
    0 [88]
    0 [89]
    Units: subjects
    Notes
    [87] - Finalized data is not available to report, and would be updated once report is finalized.
    [88] - Finalized data is not available to report, and would be updated once report is finalized.
    [89] - Finalized data is not available to report, and would be updated once report is finalized.
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with the BRAF loci Mutational Status

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    End point title
    		 Number of subjects with the BRAF loci Mutational Status
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment until 134 weeks assessed every 8 weeks
    End point values
    		 Refametinib (BAY86-9766), 30 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Number of subjects analysed
    0 [90]
    0 [91]
    0 [92]
    Units: subjects
    Notes
    [90] - Finalized data is not available to report, and would be updated once report is finalized.
    [91] - Finalized data is not available to report, and would be updated once report is finalized.
    [92] - Finalized data is not available to report, and would be updated once report is finalized.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after last dose
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Refametinib (BAY86-9766), 50 mg twice daily, Phase I
    Reporting group description
    		 Refametinib was administered orally on Day 2 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Refametinib (BAY86-9766), 50 mg twice daily, Phase II
    Reporting group description
    		 Refametinib was administered orally on Day 1 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 IV infusion dose over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Refametinib (BAY86-9766), 30 mg twice daily, Phase I
    Reporting group description
    		 Refametinib was administered orally on Day 2 at a dose of 30 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Serious adverse events
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase II Refametinib (BAY86-9766), 30 mg twice daily, Phase I
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    48 / 70 (68.57%)
    7 / 10 (70.00%)
         number of deaths (all causes)
    7
    40
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 70 (5.71%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis infected
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 70 (5.71%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Refametinib (BAY86-9766), 50 mg twice daily, Phase I Refametinib (BAY86-9766), 50 mg twice daily, Phase II Refametinib (BAY86-9766), 30 mg twice daily, Phase I
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    69 / 70 (98.57%)
    10 / 10 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 70 (11.43%)
    1 / 10 (10.00%)
         occurrences all number
    1
    9
    1
    Axillary vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences all number
    2
    3
    0
    Hypertension
         subjects affected / exposed
    3 / 10 (30.00%)
    7 / 70 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    12
    36
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 70 (4.29%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    0
    Fatigue
         subjects affected / exposed
    3 / 10 (30.00%)
    33 / 70 (47.14%)
    8 / 10 (80.00%)
         occurrences all number
    5
    82
    20
    Asthenia
         subjects affected / exposed
    0 / 10 (0.00%)
    9 / 70 (12.86%)
    0 / 10 (0.00%)
         occurrences all number
    0
    20
    0
    Oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 70 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    7
    1
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 70 (2.86%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Malaise
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    15 / 70 (21.43%)
    0 / 10 (0.00%)
         occurrences all number
    0
    42
    0
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    2
    Pyrexia
         subjects affected / exposed
    6 / 10 (60.00%)
    26 / 70 (37.14%)
    4 / 10 (40.00%)
         occurrences all number
    10
    46
    8
    Oedema peripheral
         subjects affected / exposed
    2 / 10 (20.00%)
    39 / 70 (55.71%)
    7 / 10 (70.00%)
         occurrences all number
    2
    84
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    11 / 70 (15.71%)
    1 / 10 (10.00%)
         occurrences all number
    2
    14
    1
    Alveolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    0 / 10 (0.00%)
         occurrences all number
    0
    4
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    5
    0
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    19 / 70 (27.14%)
    0 / 10 (0.00%)
         occurrences all number
    2
    32
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 70 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    1
    6
    0
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 70 (11.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    8
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 70 (4.29%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    0
    Hallucination
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    1
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 70 (11.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    9
    0
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    1 / 10 (10.00%)
         occurrences all number
    0
    6
    1
    Sleep disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood albumin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    21 / 70 (30.00%)
    3 / 10 (30.00%)
         occurrences all number
    6
    73
    12
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    25 / 70 (35.71%)
    4 / 10 (40.00%)
         occurrences all number
    5
    74
    18
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    14 / 70 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    6
    40
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences all number
    0
    8
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences all number
    0
    6
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    3
    Neutrophil count decreased
         subjects affected / exposed
    3 / 10 (30.00%)
    10 / 70 (14.29%)
    3 / 10 (30.00%)
         occurrences all number
    6
    38
    10
    Lipase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    10
    0
    Protein total decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Prothrombin time shortened
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    22 / 70 (31.43%)
    4 / 10 (40.00%)
         occurrences all number
    4
    62
    22
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    22
    16
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    1
    Head injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 10 (0.00%)
    10 / 70 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    0
    10
    0
    Burning sensation mucosal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 10 (20.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences all number
    2
    7
    1
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 70 (4.29%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    0
    Epilepsy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Encephalopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Presyncope
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 70 (4.29%)
    0 / 10 (0.00%)
         occurrences all number
    1
    4
    0
    Somnolence
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    6
    1
    Syncope
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 70 (5.71%)
    0 / 10 (0.00%)
         occurrences all number
    2
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    40 / 70 (57.14%)
    4 / 10 (40.00%)
         occurrences all number
    2
    178
    29
    Leukopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    9 / 70 (12.86%)
    0 / 10 (0.00%)
         occurrences all number
    0
    47
    0
    Neutropenia
         subjects affected / exposed
    1 / 10 (10.00%)
    26 / 70 (37.14%)
    4 / 10 (40.00%)
         occurrences all number
    1
    121
    27
    Thrombocytopenia
         subjects affected / exposed
    2 / 10 (20.00%)
    30 / 70 (42.86%)
    2 / 10 (20.00%)
         occurrences all number
    3
    118
    6
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences all number
    0
    17
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Retinopathy hypertensive
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    19 / 70 (27.14%)
    1 / 10 (10.00%)
         occurrences all number
    4
    26
    5
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    9 / 70 (12.86%)
    1 / 10 (10.00%)
         occurrences all number
    0
    16
    1
    Aphthous stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Constipation
         subjects affected / exposed
    3 / 10 (30.00%)
    15 / 70 (21.43%)
    2 / 10 (20.00%)
         occurrences all number
    3
    18
    3
    Ascites
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences all number
    0
    11
    1
    Dry mouth
         subjects affected / exposed
    2 / 10 (20.00%)
    9 / 70 (12.86%)
    0 / 10 (0.00%)
         occurrences all number
    3
    13
    0
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    7 / 70 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    9
    2
    Faecal incontinence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 10 (30.00%)
    34 / 70 (48.57%)
    4 / 10 (40.00%)
         occurrences all number
    5
    59
    9
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    3 / 10 (30.00%)
         occurrences all number
    0
    3
    3
    Nausea
         subjects affected / exposed
    6 / 10 (60.00%)
    33 / 70 (47.14%)
    6 / 10 (60.00%)
         occurrences all number
    10
    66
    9
    Vomiting
         subjects affected / exposed
    4 / 10 (40.00%)
    31 / 70 (44.29%)
    2 / 10 (20.00%)
         occurrences all number
    9
    61
    3
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    11 / 70 (15.71%)
    0 / 10 (0.00%)
         occurrences all number
    1
    20
    0
    Regurgitation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Liver injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Portal vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 10 (0.00%)
    8 / 70 (11.43%)
    0 / 10 (0.00%)
         occurrences all number
    0
    8
    0
    Acne
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    2
    Dry skin
         subjects affected / exposed
    2 / 10 (20.00%)
    7 / 70 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    13
    1
    Dermatitis acneiform
         subjects affected / exposed
    3 / 10 (30.00%)
    9 / 70 (12.86%)
    1 / 10 (10.00%)
         occurrences all number
    5
    19
    2
    Nail bed inflammation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    2 / 10 (20.00%)
         occurrences all number
    0
    10
    2
    Onychoclasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    2 / 10 (20.00%)
    6 / 70 (8.57%)
    0 / 10 (0.00%)
         occurrences all number
    2
    11
    0
    Rash
         subjects affected / exposed
    6 / 10 (60.00%)
    44 / 70 (62.86%)
    4 / 10 (40.00%)
         occurrences all number
    14
    135
    16
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    6 / 70 (8.57%)
    2 / 10 (20.00%)
         occurrences all number
    1
    7
    2
    Muscular weakness
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    0 / 10 (0.00%)
         occurrences all number
    0
    5
    0
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    9 / 70 (12.86%)
    1 / 10 (10.00%)
         occurrences all number
    0
    12
    1
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Folliculitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Genital candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 70 (8.57%)
    1 / 10 (10.00%)
         occurrences all number
    0
    8
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 70 (2.86%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 70 (11.43%)
    1 / 10 (10.00%)
         occurrences all number
    1
    9
    1
    Tracheitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 10 (20.00%)
    22 / 70 (31.43%)
    3 / 10 (30.00%)
         occurrences all number
    2
    35
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    4
    8
    Hypoglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    1 / 10 (10.00%)
         occurrences all number
    0
    8
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    15 / 70 (21.43%)
    4 / 10 (40.00%)
         occurrences all number
    1
    23
    13
    Hypomagnesaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    2 / 10 (20.00%)
         occurrences all number
    0
    9
    5
    Hypophosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Vitamin D deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Vitamin K deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2011
    Amendment 1 included new data from preclinical and clinical trials and revised the informed consent form for genetic testing due to regulatory requirements / requests. In addition, inconsistencies and errors were corrected, and clarifications to the original protocol were made. In Amendment 1, the protocol was: 1. Revised to indicate that drug-drug interactions with substrates of CYP2C8 cannot be ruled out. Caution was recommended when considering or administering medications that are metabolized by cytochrome enzyme CYP2C8 (eg, repaglinide and torsemide). Such concomitant medications were to be avoided, if possible. 2. Revised to include additions of two new exclusion criteria: to exclude patients with history or current retinal vein occlusion or retinopathy; or retinal pathology considered a risk factor for these conditions. This change was made to be consistent with exclusion criteria in other MEK-inhibitor studies. 3. Revised to indicate that both gemcitabine and refametinib seem to have a largely non-overlapping adverse event (AE) profile. An additional recommendation was given regarding the necessity for careful observation of the intensity and frequency of AEs (side effects) as well as the occurrence of new and unexpected AEs for the combination of the drugs administered to the patients. 4. Revised to add a separate genetic informed consent. Also, a baseline blood plasma sample for mutational analysis is not to be collected from patients who reside in countries that require a separate genetic consent form, and fail to provide genetic consent. 5. Revised to add a new table regarding dose adjustments and treatment interruptions triggered by transaminase elevations.
    26 Apr 2012
    Amendment 2 introduced a more intensive treatment for skin toxicity, added Creatine phosphokinase (CPK) examinations to the chemistry panel, removed Cycle 1 Day 50 and Cycle 2 Day 22 from the schedule of examinations and clarified ophthalmologic examinations, exclusion criteria and echocardiography assessments. In addition, inconsistencies and errors were corrected and clarifications were made. In Amendment 2, the protocol was: 1. Revised to include the application of systemic antibiotics for skin toxicity CTCAE Grade 1. 2. Revised to add CPK examination to the chemistry panel, scheduled to be performed at screening, weekly within the first 4 weeks, afterwards every 2 weeks. Closer evaluations in case of CTCAE Grade 3 elevations were required. Dose modifications were required in case of CPK increase greater than or equal to (>=) CTCAE Grade 3 for refametinib. 3. Revised to include CPK increase > CTCAE Grade 3 as adverse event of special interest. 4. Revised to reduce the number of visits on days patients do not require a full in-hospital visit (Cycle 1 Day 50 and Cycle 2 Day 22). 5. Revised to change the day of ophthalmologic examination to within 8 days (+/-) from Cycle 1 Day 43. 6. Revised to extend the time required for adequate contraception from 3 months to 6 months after last study treatment. 7. Revised to specify that echocardiography assessments should be performed by an experienced qualified technician or cardiologist and should be evaluated by an experienced cardiologist. The expression experienced “investigator” is not correct.
    13 May 2013
    Amendment 3 reduced the number of efficacy and safety measurements performed after the primary completion date. 1. Reduced the frequency of tumor assessments from every 8 weeks to every 12 weeks. 2. Specified that beyond the cut-off date for the final analysis, safety data (AEs of CTCAE Grades 3 and 4 and Serious AEs) for each patient continuing on study drug would be captured until 30 days after the individual patient had stopped study treatment. 3. Eliminated the need to (1) collect diary and records of pain medication taken before patient’s visit to study site, and (2) collect blood plasma samples for end of treatment analysis for determination of the apoptosis marker cleaved cytokeratin 18 (CK18) "M30" and possibly other biomarkers of tumor response, after Amendment 3 became effective.

    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.
    '99999' in the posting indicates that data were not calculated. Decimal places were automatically truncated if last decimal equals zero.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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