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    Clinical Trial Results:
    A Phase II uncontrolled study of BAY73-4506 in previously untreated patients with metastatic or unresectable renal cell cancer (RCC)

    Summary
    EudraCT number
    2008-000107-28
    Trial protocol
    FI   DE   FR   GB  
    Global end of trial date
    02 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Apr 2020
    First version publication date
    09 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    11726/BAY73-4506
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00664326
    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
    24 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the antitumor activity and safety of BAY 73-4506 in previously untreated subjects with metastatic or unresectable RCC. Secondary objectives included the evaluation of pharmacokinetic and biomarker data.
    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. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Apr 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Poland: 8
    Worldwide total number of subjects
    49
    EEA total number of subjects
    47
    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)
    31
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Male or female untreated participants, who were at least 18 years of age, with metastatic and/or unresectable, measurable predominantly clear cell renal cell cancer (RCC) histologically or cytologically documented could participate in this study at 18 centers in 6 countries.

    Pre-assignment
    Screening details
    Of 64 enrolled participants, 49 received study medication, and 15 were screen failures due to protocol violation (12 participants), withdrawal of consent (1 participant), adverse event (2 participants).

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

    Arms
    Arm title
    Regorafenib (Stivarga, BAY73-4506)
    Arm description
    Participants received Regorafenib 160 mg per os (po) every day (qd) for 3 weeks on 1 week off of every 4 week cycle
    Arm type
    Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY73-4506
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BAY 73-4506, 160 mg once daily for 3 weeks of every 4-week cycle (i.e., 3 weeks on, 1 week off)

    Number of subjects in period 1
    Regorafenib (Stivarga, BAY73-4506)
    Started
    49
    Completed
    1
    Not completed
    48
         Disease Progression, Recurrence, or Relapse
    24
         Physician decision
    1
         Adverse event, serious fatal
    2
         Other Reasons
    3
         Non-compliant with Study Medication
    3
         Adverse event, non-fatal
    14
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regorafenib (Stivarga, BAY73-4506)
    Reporting group description
    Participants received Regorafenib 160 mg per os (po) every day (qd) for 3 weeks on 1 week off of every 4 week cycle

    Reporting group values
    Regorafenib (Stivarga, BAY73-4506) Total
    Number of subjects
    49 49
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    31 31
        From 65-84 years
    18 18
        85 years and over
    0 0
    Age Continuous
    Units: Years
        median (full range (min-max))
    62.0 (40 to 76) -
    Sex: Female, Male
    Units:
        Female
    22 22
        Male
    27 27
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    The ECOG PS ranged from Grades 0 to 5 (death). Grade 0 (fully active, able to carry on all pre-diseases performance without restriction) and Grade 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) were inclusion criteria.
    Units: Subjects
        PS 0
    30 30
        PS 1
    19 19
    Overall Motzer Score
    The Motzer score (high/poor risk, intermediate risk, low risk) is based on the number of the following poor prognostic features a participant possessed: ECOG >2, serum lactate dehydrogenase concentration > 1.5 times the upper limit of normal, hemoglobin < lower limit of normal, corrected calcium concentration > 10 mg/dl, and absence of prior nephrectomy. Participants who had none of these features = low risk; participants with 1 or 2 of these features = intermediate risk; participants with 3 or more of these features = high/poor risk and were excluded from participating in the study.
    Units: Subjects
        Low
    24 24
        Intermediate
    25 25

    End points

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    End points reporting groups
    Reporting group title
    Regorafenib (Stivarga, BAY73-4506)
    Reporting group description
    Participants received Regorafenib 160 mg per os (po) every day (qd) for 3 weeks on 1 week off of every 4 week cycle

    Primary: Objective tumor response

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    End point title
    Objective tumor response [1]
    End point description
    Objective tumor response of a participant was defined as the best tumor response (confirmed Complete Response [CR, tumor disappears] or Partial Response [PR, sum of lesion sizes decreased at least 30% from baseline]) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) committee.
    End point type
    Primary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    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: Statistical analyses of this primary endpoint is descriptive
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    48
    Units: Percentage of participants
        number (not applicable)
    31.3
    No statistical analyses for this end point

    Primary: Tumor response

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    End point title
    Tumor response [2]
    End point description
    Tumor response of a participant was defined as the best tumor response (confirmed Complete Response [CR, tumor disappears], Partial Response [PR, sum of lesion sizes decreased at least 30% from baseline], Stable Disease [SD, steady state of disease], or Progressive Disease [PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions]) observed during trial period assessed according to the RECIST committee.
    End point type
    Primary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses of this primary endpoint is descriptive.
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    48
    Units: Percentage of participants
    number (not applicable)
        Complete Response (CR)
    0.0
        Partial Response (PR)
    31.3
        Stable Disease (SD)
    50.0
        Progressive Disease (PD)
    10.4
        Not Assessable
    8.3
    No statistical analyses for this end point

    Secondary: Disease control

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    End point title
    Disease control
    End point description
    Disease control was defined as the percentage of participants who had a best response rating of CR (tumor disappears), PR (sum of lesion sizes decreased at least 30% from baseline), or SD (steady state of disease) that was maintained for at least 28 days from the first demonstration of that rating.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    48
    Units: Percentage of participants
        number (not applicable)
    62.5
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival (OS) was calculated as the time from the first date of receiving study medication to death, due to any cause. Participants alive at the time of analysis were censored at their last date of follow-up.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009).
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    49
    Units: Days
        median (confidence interval 95%)
    99999 (285 to 99999)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    PFS was calculated as time from first date of receiving study drug until date of first observed disease progression (PD) (radiological or clinical, whichever was earlier) or death due to any cause, if death occurred before PD was documented. The actual date of tumor assessments (i.e., date on which radiological procedure was performed, rather than scheduled date) was used for this calculation to determine both the event date and censoring date. Patients without PD or death at time of analysis were censored at last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    49
    Units: Days
        median (confidence interval 95%)
    251 (160 to 99999)
    No statistical analyses for this end point

    Secondary: Time to progression (TTP)

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    End point title
    Time to progression (TTP)
    End point description
    TTP was calculated as time from first date of receiving study drug until date of first documented disease progression (PD) (radiological or clinical, whichever was earlier). The actual date of tumor assessments (i.e., date on which radiological procedure was performed, rather than the scheduled date) was used for this calculation to determine both the event date and censoring date. Patients without PD at time of analysis were censored at last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    49
    Units: Days
        median (confidence interval 95%)
    251 (167 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    Duration of response
    End point description
    Duration of response was defined as the time from the first documented objective response of PR or CR, whichever was earlier, to disease progression or death (if death occurred before progression was documented). Duration of response for subjects who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    15
    Units: Days
        median (confidence interval 95%)
    99999 (140 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of stable disease (SD)

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    End point title
    Duration of stable disease (SD)
    End point description
    Duration of SD was calculated as the time from the first date of receiving study drug until the date of documented PD or the last observation if the subject did not progress. Subjects without disease progression at the time of analysis were censored at the last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 13 months later (13May2008 - 31May2009). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    29
    Units: Days
        median (confidence interval 95%)
    172 (107 to 99999)
    No statistical analyses for this end point

    Other pre-specified: Objective tumor response (Update)

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    End point title
    Objective tumor response (Update)
    End point description
    Objective tumor response of a participant was defined as the best tumor response (confirmed Complete Response [CR, tumor disappears] or Partial Response [PR, sum of lesion sizes decreased at least 30% from baseline]) observed during trial period assessed according to the RECIST committee.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    48
    Units: Percentage of participants
        number (not applicable)
    39.6
    No statistical analyses for this end point

    Other pre-specified: Tumor response (Update)

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    End point title
    Tumor response (Update)
    End point description
    Tumor response of a participant was defined as the best tumor response (confirmed Complete Response [CR, tumor disappears], Partial Response [PR, sum of lesion sizes decreased at least 30% from baseline], Stable Disease [SD, steady state of disease], or Progressive Disease [PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions]) observed during trial period assessed according to the RECIST committee.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    48
    Units: Percentage of participants
    number (not applicable)
        Complete Response (CR)
    0.0
        Partial Response (PR)
    39.6
        Stable Disease (SD)
    41.7
        Progressive Disease (PD)
    10.4
        Not Assessable
    8.3
    No statistical analyses for this end point

    Other pre-specified: Disease control (Update)

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    End point title
    Disease control (Update)
    End point description
    Disease control was defined as the percentage of participants who had a best response rating of CR (tumor disappears), PR (sum of lesion sizes decreased at least 30% from baseline), or SD (steady state of disease) that was maintained for at least 28 days from the first demonstration of that rating.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    48
    Units: Percentage of participants
        number (not applicable)
    62.5
    No statistical analyses for this end point

    Other pre-specified: Overall survival (Update)

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    End point title
    Overall survival (Update)
    End point description
    Overall survival (OS) was calculated as the time from the first date of receiving study medication to death, due to any cause. Participants alive at the time of analysis were censored at their last date of follow-up.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011).
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    49
    Units: Days
        median (confidence interval 95%)
    99999 (735 to 99999)
    No statistical analyses for this end point

    Other pre-specified: Progression-free survival (Update)

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    End point title
    Progression-free survival (Update)
    End point description
    PFS was calculated as time from first date of receiving study drug until date of first observed disease progression (PD) (radiological or clinical, whichever was earlier) or death due to any cause, if death occurred before PD was documented. The actual date of tumor assessments (i.e., date on which radiological procedure was performed, rather than scheduled date) was used for this calculation to determine both the event date and censoring date. Patients without PD or death at time of analysis were censored at last date of tumor evaluation.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    49
    Units: Days
        median (confidence interval 95%)
    335 (167 to 438)
    No statistical analyses for this end point

    Other pre-specified: Time to progression (Update)

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    End point title
    Time to progression (Update)
    End point description
    TTP was calculated as time from first date of receiving study drug until date of first documented disease progression (PD) (radiological or clinical, whichever was earlier). The actual date of tumor assessments (i.e., date on which radiological procedure was performed, rather than the scheduled date) was used for this calculation to determine both the event date and censoring date. Patients without PD at time of analysis were censored at last date of tumor evaluation.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    49
    Units: Days
        median (confidence interval 95%)
    335 (167 to 454)
    No statistical analyses for this end point

    Other pre-specified: Duration of response (Update)

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    End point title
    Duration of response (Update)
    End point description
    Duration of response was defined as the time from the first documented objective response of PR or CR, whichever was earlier, to disease progression or death (if death occurred before progression was documented). Duration of response for subjects who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    19
    Units: Days
        median (confidence interval 95%)
    428 (250 to 540)
    No statistical analyses for this end point

    Other pre-specified: Duration of stable disease (Update)

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    End point title
    Duration of stable disease (Update)
    End point description
    Duration of SD was calculated as the time from the first date of receiving study drug until the date of documented PD or the last observation if the subject did not progress. Subjects without disease progression at the time of analysis were censored at the last date of tumor evaluation.
    End point type
    Other pre-specified
    End point timeframe
    From start of treatment of the first participant until database cut-off approximately 37 months later (13May2008 - 1Jun2011). Assessed every 8 weeks for 6 months, then every 12 weeks
    End point values
    Regorafenib (Stivarga, BAY73-4506)
    Number of subjects analysed
    25
    Units: Days
        median (confidence interval 95%)
    119 (105 to 335)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment up to 30 days after the last dose of study drug
    Adverse event reporting additional description
    Acronyms used in Adverse events section: Gastrointestinal (GI), Not Otherwise Specified (NOS), Absolute Neutrophil Count (ANC), Common Terminology Criteria for Adverse Events (CTCAE).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Regorafenib (BAY73-4506)
    Reporting group description
    Subjects received regorafenib 160 mg po qd for 3 weeks of every 4 week cycle (3 weeks on, 1 week off).

    Serious adverse events
    Regorafenib (BAY73-4506)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 49 (65.31%)
         number of deaths (all causes)
    39
         number of deaths resulting from adverse events
    5
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Tumour excision
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone neoplasm
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    2 / 2
    Myocardial infarction
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Laryngospasm
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Regorafenib (BAY73-4506)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 49 (97.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    25 / 49 (51.02%)
         occurrences all number
    338
    Investigations
    Amylase increased
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    12
    Weight decreased
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    86
    Blood creatinine increased
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    7
    Lipase increased
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    29
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    11
    Anaemia
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    15
    Dysphonia
         subjects affected / exposed
    18 / 49 (36.73%)
         occurrences all number
    50
    Dyspnoea
         subjects affected / exposed
    16 / 49 (32.65%)
         occurrences all number
    48
    Oropharyngeal pain
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    7
    Epistaxis
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    7
    Ageusia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    14
    Neuropathy peripheral
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    14 / 49 (28.57%)
         occurrences all number
    47
    Paraesthesia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    61
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 49 (44.90%)
         occurrences all number
    192
    Chest pain
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    19
    Mucosal inflammation
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    11
    Chills
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    6
    Oedema peripheral
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    13
    Pain
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    31
    Pyrexia
         subjects affected / exposed
    9 / 49 (18.37%)
         occurrences all number
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    23
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    17 / 49 (34.69%)
         occurrences all number
    112
    Dysphagia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    16 / 49 (32.65%)
         occurrences all number
    46
    Vomiting
         subjects affected / exposed
    13 / 49 (26.53%)
         occurrences all number
    29
    Abdominal pain
         subjects affected / exposed
    13 / 49 (26.53%)
         occurrences all number
    37
    Abdominal pain upper
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    28
    Diarrhoea
         subjects affected / exposed
    24 / 49 (48.98%)
         occurrences all number
    215
    Dyspepsia
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    7
    Glossodynia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Oral pain
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    35
    Stomatitis
         subjects affected / exposed
    15 / 49 (30.61%)
         occurrences all number
    108
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    22 / 49 (44.90%)
         occurrences all number
    139
    Pruritus
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    16
    Dry skin
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    77
    Hyperhidrosis
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    19
    Night sweats
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    8
    Palmar erythema
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    34 / 49 (69.39%)
         occurrences all number
    402
    Rash
         subjects affected / exposed
    17 / 49 (34.69%)
         occurrences all number
    74
    Rash generalised
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 49 (26.53%)
         occurrences all number
    55
    Arthralgia
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    120
    Musculoskeletal pain
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    23
    Bone pain
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    25
    Muscle spasms
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    53
    Neck pain
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    12
    Pain in extremity
         subjects affected / exposed
    11 / 49 (22.45%)
         occurrences all number
    85
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    13
    Decreased appetite
         subjects affected / exposed
    16 / 49 (32.65%)
         occurrences all number
    104
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    6
    Nasopharyngitis
         subjects affected / exposed
    9 / 49 (18.37%)
         occurrences all number
    21
    Infection
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Bronchitis
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    6
    Oral candidiasis
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2008
    A Data Monitoring Committee was added. Clarification was provided for how the risk/benefit was to be assessed during the study and how the termination/continuation would be evaluated. The frequency of tumor assessments after month 6 (cycle 6) was decreased from every 8 weeks to every 12 weeks. The timing of disease assessments was clarified. The packaging configuration for study medication was added. Assessments (tissue and blood biomarker samples, vital signs, blood pressure, and laboratory evaluations) were clarified. The description of Adverse Events handling was updated to reflect Bayer oncology standards. Pharmacokinetic Sample Handling Instructions were removed to avoid duplication of instructions that were already present in a separate Laboratory Manual.
    19 Aug 2008
    Subjects who remained on treatment following disease progression were no longer required to undergo radiological evaluations for the purpose of tumor response assessment. Describe changes to the 20mg tablet formulation and add the 40mg tablet formulation. Background safety data was updated.
    30 Jan 2009
    Subjects who had disease progression while receiving study drug were allowed to remain on treatment if the investigator and sponsor felt that the subject would benefit.
    05 Jun 2009
    Subjects were required to undergo a full urinalysis, rather than dipstick. Additionally, the frequency of urinalysis, chemistry, and electrolyte panels was increased to every 2 weeks instead of at the beginning of each 4-week cycle.
    02 Dec 2010
    Clarified that Day 15 laboratory assessments were not required after 6 cycles of treatment if the subject continued to receive clinical benefit from treatment and there were no clinically significant laboratory abnormalities.
    15 Jul 2011
    The purpose of Amendment 6, a global amendment, was to increase liver function test monitoring and include a dose modification table for AST, ALT and bilirubin in the protocol.
    04 Dec 2012
    The purpose of Amendment 7, a global amendment, was to allow for less frequent imaging procedures and laboratory assessment for patients who have been on treatment for more than 2 years (24 cycles).

    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.
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