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    Clinical Trial Results:
    A Randomized, Double Blinded, Multi-Center Phase 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination With AMG 386 or Placebo in Subjects With Metastatic Clear Cell Carcinoma of the Kidney

    Summary
    EudraCT number
    2007-000147-98
    Trial protocol
    FR   BE   AT  
    Global end of trial date
    10 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20060159
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00467025
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    10 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to estimate the efficacy as measured by progression-free survival (PFS) of subjects receiving trebananib in combination with sorafenib compared to subjects receiving sorafenib plus placebo.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 May 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    48 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 42
    Country: Number of subjects enrolled
    Poland: 67
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 26
    Worldwide total number of subjects
    152
    EEA total number of subjects
    110
    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)
    103
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible subjects were men or women ≥ 18 years of age with histologically confirmed metastatic renal cell carcinoma (RCC) with a clear cell component, of low or intermediate risk according to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk classification.

    Pre-assignment
    Screening details
    Two hundred one subjects were screened for enrollment, and 152 subjects were enrolled in the study: 51 in the Trebananib 3-mg/kg arm, 50 in the Trebananib 10-mg/kg arm, and 51 in the placebo arm. Subjects were stratified by risk classification (low vs intermediate) according to the MSKCC prognostic risk classification.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trebananib 3 mg/kg + Sorafenib
    Arm description
    Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered to subjects in all 3 arms of this clinical trial at a starting dose of 400 mg orally BID.

    Investigational medicinal product name
    Trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion once weekly

    Arm title
    Trebananib 10 mg/kg + Sorafenib
    Arm description
    Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered to subjects in all 3 arms of this clinical trial at a starting dose of 400 mg orally BID.

    Investigational medicinal product name
    Trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion once weekly

    Arm title
    Placebo + Sorafenib
    Arm description
    Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion once weekly

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered to subjects in all 3 arms of this clinical trial at a starting dose of 400 mg orally BID.

    Number of subjects in period 1
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Started
    51
    50
    51
    Received Treatment
    51
    50
    50
    Crossover to open-label trebananib
    0 [1]
    0 [2]
    32 [3]
    Completed
    51
    50
    50
    Not completed
    0
    0
    1
         Did not receive study drug
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not applicable to Trebananib 3 mg/kg + Sorafenib treatment arm
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not applicable to Trebananib 10 mg/kg + Sorafenib treatment arm
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 32 subjects crossed over to open-label trebananib (10 mg/kg IV QW) and sorafenib upon disease progression

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trebananib 3 mg/kg + Sorafenib
    Reporting group description
    Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Placebo + Sorafenib
    Reporting group description
    Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib Total
    Number of subjects
    51 50 51 152
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.8 ± 10.9 60.7 ± 8.9 59.7 ± 10.1 -
    Gender categorical
    Units: Subjects
        Female
    16 9 13 38
        Male
    35 41 38 114
    Race
    Units: Subjects
        White or Caucasian
    47 49 48 144
        Black or African American
    2 0 2 4
        Hispanic or Latino
    2 1 1 4
    MSKCC Risk Classification
    The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk classification based on the following risk factors: - Karnofsky performance status < 80%; - Serum lactate dehydrogenase > 1.5 x upper limit of normal (ULN); - Serum hemoglobin < lower limit of normal (LLN) for their institutions; - Serum Calcium (corrected) > 10 mg/dL; - Time from diagnosis of RCC to first systemic treatment < 1 year. Low risk is defined as 0 risk factors; intermediate risk is defined as 1-2 risk factors.
    Units: Subjects
        Low
    20 21 21 62
        Intermediate
    31 29 30 90

    End points

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    End points reporting groups
    Reporting group title
    Trebananib 3 mg/kg + Sorafenib
    Reporting group description
    Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Placebo + Sorafenib
    Reporting group description
    Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Primary: Progression-Free Survival

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    End point title
    Progression-Free Survival
    End point description
    Progression-free survival is calculated as the time between the randomization of protocol-specified treatment to the earliest date disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria or death, assessed by the Investigator. Progression-free survival was analyzed using the Kaplan-Meier method. Subjects who had not died and did not have an assessment of disease progression were censored at their last evaluable disease assessment date.
    End point type
    Primary
    End point timeframe
    Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the cut-off date of 28 February 2013; median time on study was 113 weeks.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    51
    50
    51
    Units: months
        median (confidence interval 80%)
    8.5 (7.2 to 9.1)
    9 (5.6 to 11)
    9 (7.2 to 9.2)
    Statistical analysis title
    Trebananib combined versus placebo
    Statistical analysis description
    A Cox regression model stratified by MSKCC prognostic risk classification was used to estimate the progression-free survival hazard ratio and 2-sided 80% confidence interval for both trebananib + sorafenib dose groups combined versus placebo + sorafenib. A hazard ratio of < 1.0 indicates a lower average event rate and longer time to event for the trebananib treatment group relative to the placebo group.
    Comparison groups
    Trebananib 3 mg/kg + Sorafenib v Trebananib 10 mg/kg + Sorafenib v Placebo + Sorafenib
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.97 [1]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.993
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.782
         upper limit
    1.261
    Notes
    [1] - No adjustments for multiple testing were used. Stratifed by MSKCC risk category.

    Secondary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    Objective Response Rate (ORR) defined as either a confirmed complete response (CR) or partial response (PR) per modified RECIST (v 1.0) criteria (responder). A confirmed CR requires 2 assessments of CR at least 28 days apart. A confirmed PR requires 2 assessments at least 28 days apart of PR or CR. All subjects who did not meet the criteria for an objective response by the analysis cutoff date were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the cut-off date of 28 February 2013; median time on study was 113 weeks.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    51 [2]
    50 [3]
    51 [4]
    Units: percentage of subjects
        number (confidence interval 80%)
    37 (28 to 47)
    40 (31 to 50)
    27 (19 to 37)
    Notes
    [2] - Subjects with measurable disease at baseline
    [3] - Subjects with measurable disease at baseline
    [4] - Subjects with measurable disease at baseline
    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 calculated only for those subjects with an objective response and is defined as the time from first confirmed objective response to first observed disease progression or death due to any cause. Subjects not meeting criteria for progression by the analysis data cutoff date or who had not died were censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method. "99999" indicates data not estimable.
    End point type
    Secondary
    End point timeframe
    Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the primary analysis cut-off date of February 2010; median time on study was 75 weeks.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    19 [5]
    19 [6]
    13 [7]
    Units: months
        median (confidence interval 80%)
    7.4 (6.9 to 13)
    8.9 (7.4 to 99999)
    8.9 (7.4 to 12.9)
    Notes
    [5] - Subjects with a response
    [6] - Subjects with a response
    [7] - Subjects with a response
    No statistical analyses for this end point

    Secondary: Change in Tumor Burden

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    End point title
    Change in Tumor Burden
    End point description
    Reduction in tumor burden was measured as the maximum percent reduction from Baseline (or, for subjects without a reduction, the minimum increase from Baseline) in the sum of the longest diameters (SLD) of target lesions. For each subject the maximum percent reduction in SLD from baseline to the post-baseline nadir was identified, and the mean of these values was then calculated.
    End point type
    Secondary
    End point timeframe
    Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the primary analysis cut-off date of 22 February 2010; median time on study was 72 weeks.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    47 [8]
    46 [9]
    47 [10]
    Units: percent reduction
        arithmetic mean (confidence interval 80%)
    -29.2 (-33.5 to -24.9)
    -34.3 (-38.6 to -30)
    -23.8 (-28 to -19.7)
    Notes
    [8] - Subjects with available data
    [9] - Subjects with available data
    [10] - Subjects with available data
    No statistical analyses for this end point

    Secondary: Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

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    End point title
    Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score
    End point description
    The FKSI-15 is a validated symptom index for kidney cancer patients containing 15 questions, each scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-15 summary score ranges from 0 to 60, with higher scores indicating less severe symptoms or concerns. The AUC was calculated using the trapezoidal rule and divided by the duration in weeks of the assessment period to obtain the time-adjusted AUC. The patient-reported outcomes (PRO) analysis set includes all subjects with at least one PRO assessment prior to disease progression.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 57
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    51 [11]
    49 [12]
    50 [13]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -2 (-3.5 to -0.5)
    -0.9 (-2.4 to 0.6)
    -2.4 (-3.9 to -0.9)
    Notes
    [11] - PRO analysis set
    [12] - PRO analysis set
    [13] - PRO analysis set
    Statistical analysis title
    Difference Between Trebananib 3 mg/kg and 10 mg/kg
    Statistical analysis description
    Mixed model analysis including fixed effects for treatment, visit, baseline PRO scale score, the interaction of treatment and visit, and a subject-specific random intercept.
    Comparison groups
    Trebananib 10 mg/kg + Sorafenib v Trebananib 3 mg/kg + Sorafenib
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    3.2
    Statistical analysis title
    Difference Between Trebananib 10 mg/kg and Placebo
    Statistical analysis description
    Mixed model analysis including fixed effects for treatment, visit, baseline PRO scale score, the interaction of treatment and visit, and a subject-specific random intercept.
    Comparison groups
    Trebananib 10 mg/kg + Sorafenib v Placebo + Sorafenib
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    3.6
    Statistical analysis title
    Difference Between Trebananib 3 mg/kg and Placebo
    Statistical analysis description
    Mixed model analysis including fixed effects for treatment, visit, baseline PRO scale score, the interaction of treatment and visit, and a subject-specific random intercept.
    Comparison groups
    Placebo + Sorafenib v Trebananib 3 mg/kg + Sorafenib
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    2.5

    Secondary: Number of Subjects With Adverse Events (AE)

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    End point title
    Number of Subjects With Adverse Events (AE)
    End point description
    Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose of any study therapy. Median duration of trebananib treatment was 8.0, 9.5 and 9.5 months in each treatment group respectively.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    51 [14]
    50 [15]
    50 [16]
    Units: subjects
        Any adverse event
    50
    49
    50
        Worst grade of 3
    29
    28
    38
        Worst grade of 4
    7
    4
    5
        Worst grade of 5
    1
    3
    0
        Any serious adverse event
    26
    20
    13
        Leading to discontinuation from therapy or study
    7
    8
    3
        Any treatment-related adverse event
    49
    48
    47
        Treatment-related worst grade of 3
    27
    25
    39
        Treatment-related worst grade of 4
    4
    4
    2
        Treatment-related worst grade of 5
    1
    0
    0
        Serious treatment-related AE
    16
    14
    7
        Treatment-related leading to discontinuation
    6
    5
    2
    Notes
    [14] - Safety analysis set
    [15] - Safety analysis set
    [16] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

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    End point title
    Number of Subjects with Grade 3 or Higher Laboratory Toxicities
    End point description
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until the last dose.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    51 [17]
    50 [18]
    50 [19]
    Units: subjects
        Alanine amino transferase increased
    1
    1
    2
        Albumin decreased
    1
    0
    0
        Alkaline phosphatase increased
    1
    0
    1
        Amylase increased
    3
    3
    0
        Aspartate amino transferase increased
    1
    1
    2
        Bicarbonate decreased
    0
    1
    0
        Calcium decreased
    1
    3
    2
        Creatinine increased
    0
    1
    0
        Glucose increased
    2
    3
    1
        Lipase increased
    3
    10
    3
        Magnesium decreased
    1
    2
    0
        Phosphorus decreased
    12
    9
    9
        Potassium increased
    1
    1
    3
        Potassium decreased
    4
    4
    0
        Sodium decreased
    2
    3
    0
        Absolute neutrophil count decreased
    1
    0
    1
        Hemoglobin decreased
    1
    0
    2
        Lymphocytes decreased
    5
    1
    2
        Partial thromboplastin time increased
    0
    0
    1
        Platelets decreased
    0
    0
    1
        Segmented neutrophils decreased
    1
    0
    0
        Total neutrophils decreased
    0
    0
    1
        White blood cells decreased
    0
    0
    0
    Notes
    [17] - Safety analysis set
    [18] - Safety analysis set
    [19] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

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    End point title
    Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline
    End point description
    Serum samples were first tested in an electrochemiluminescent immunoassay to detect and confirm the presence of antibodies capable of binding to trebananib. Samples that tested positive in the immunoassay were then subjected to an electrochemiluminescent receptor-binding assay to detect neutralizing or inhibitory effects of the antibodies in vitro. If a sample was positive in both assays, a subject was defined as positive for neutralizing antibodies. Additionally, if a sample was positive in the immunoassay, but negative in the receptor-binding assay, the sample was defined as positive for binding antibodies.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Cycle 3 (Week 9), and every 4 cycles (16 weeks) thereafter.
    End point values
    Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Placebo + Sorafenib
    Number of subjects analysed
    48 [20]
    48 [21]
    46 [22]
    Units: subjects
        Binding antibody positive
    2
    1
    3
        Neutralizing antibody positive
    0
    0
    0
    Notes
    [20] - Subjects with a postbaseline result
    [21] - Subjects with a postbaseline result
    [22] - Subjects with a postbaseline result
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until 30 days after the last dose of any study therapy or up to the day before first dose of open-label trebananib. For crossover subjects, from start of open-label therapy until 30 days after the last dose of trebananib.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo + Sorafenib
    Reporting group description
    Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Trebananib 3 mg/kg + Sorafenib
    Reporting group description
    Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

    Reporting group title
    Open-label Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Subjects initially randomized to Placebo + Sorafenib who discontinued treatment due to disease progression crossed over and received trebananib 10 mg/kg by intravenous infusion once a week and the same dose of sorafenib that they were receiving immediately prior to documentation of disease progression.

    Serious adverse events
    Placebo + Sorafenib Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Open-label Trebananib 10 mg/kg + Sorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 50 (26.00%)
    26 / 51 (50.98%)
    20 / 50 (40.00%)
    10 / 32 (31.25%)
         number of deaths (all causes)
    11
    31
    31
    26
         number of deaths resulting from adverse events
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    3 / 32 (9.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Metastases to spine
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tumour necrosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular neoplasm
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial restenosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incoherent
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal artery thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal vascular thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Osteomyelitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + Sorafenib Trebananib 3 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib Open-label Trebananib 10 mg/kg + Sorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    48 / 51 (94.12%)
    48 / 50 (96.00%)
    28 / 32 (87.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 50 (48.00%)
    25 / 51 (49.02%)
    22 / 50 (44.00%)
    5 / 32 (15.63%)
         occurrences all number
    38
    50
    42
    16
    Hypotension
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    4
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    6
    2
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 50 (20.00%)
    11 / 51 (21.57%)
    14 / 50 (28.00%)
    2 / 32 (6.25%)
         occurrences all number
    20
    24
    19
    2
    Chest discomfort
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Chest pain
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 51 (11.76%)
    4 / 50 (8.00%)
    4 / 32 (12.50%)
         occurrences all number
    4
    9
    6
    5
    Chills
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 51 (7.84%)
    4 / 50 (8.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    4
    6
    0
    Face oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 51 (7.84%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    5
    7
    1
    Fatigue
         subjects affected / exposed
    11 / 50 (22.00%)
    12 / 51 (23.53%)
    17 / 50 (34.00%)
    5 / 32 (15.63%)
         occurrences all number
    20
    24
    27
    8
    General physical health deterioration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Mucosal inflammation
         subjects affected / exposed
    4 / 50 (8.00%)
    10 / 51 (19.61%)
    13 / 50 (26.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    14
    25
    0
    Oedema peripheral
         subjects affected / exposed
    5 / 50 (10.00%)
    11 / 51 (21.57%)
    7 / 50 (14.00%)
    4 / 32 (12.50%)
         occurrences all number
    5
    16
    15
    4
    Pain
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 51 (1.96%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    1
    2
    0
    Pyrexia
         subjects affected / exposed
    8 / 50 (16.00%)
    5 / 51 (9.80%)
    9 / 50 (18.00%)
    0 / 32 (0.00%)
         occurrences all number
    9
    9
    15
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    5 / 50 (10.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    1
    5
    0
    Depression
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    5 / 50 (10.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    3
    6
    1
    Insomnia
         subjects affected / exposed
    3 / 50 (6.00%)
    9 / 51 (17.65%)
    12 / 50 (24.00%)
    2 / 32 (6.25%)
         occurrences all number
    7
    9
    13
    2
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    2 / 32 (6.25%)
         occurrences all number
    1
    0
    1
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    2 / 32 (6.25%)
         occurrences all number
    10
    6
    1
    4
    Amylase increased
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences all number
    6
    5
    4
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences all number
    7
    4
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 51 (1.96%)
    4 / 50 (8.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    2
    4
    0
    Blood uric acid increased
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Lipase increased
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 51 (7.84%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    7
    8
    4
    0
    Weight decreased
         subjects affected / exposed
    8 / 50 (16.00%)
    7 / 51 (13.73%)
    9 / 50 (18.00%)
    0 / 32 (0.00%)
         occurrences all number
    13
    12
    13
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    0
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 50 (10.00%)
    7 / 51 (13.73%)
    13 / 50 (26.00%)
    2 / 32 (6.25%)
         occurrences all number
    10
    7
    21
    2
    Dysphonia
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 51 (7.84%)
    6 / 50 (12.00%)
    2 / 32 (6.25%)
         occurrences all number
    2
    4
    8
    2
    Dyspnoea
         subjects affected / exposed
    6 / 50 (12.00%)
    8 / 51 (15.69%)
    10 / 50 (20.00%)
    1 / 32 (3.13%)
         occurrences all number
    12
    9
    15
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    3
    3
    1
    Epistaxis
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
    9 / 50 (18.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    11
    0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    4 / 50 (8.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Productive cough
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences all number
    3
    0
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    5 / 50 (10.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    7
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 51 (9.80%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences all number
    9
    12
    3
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    7
    3
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 51 (7.84%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    5
    4
    0
    Dysgeusia
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 51 (11.76%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    6
    2
    0
    Headache
         subjects affected / exposed
    7 / 50 (14.00%)
    10 / 51 (19.61%)
    5 / 50 (10.00%)
    2 / 32 (6.25%)
         occurrences all number
    15
    15
    8
    2
    Hyperaesthesia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Hypoaesthesia
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 51 (3.92%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences all number
    7
    7
    2
    2
    Paraesthesia
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 51 (3.92%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences all number
    7
    5
    2
    2
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
    4 / 50 (8.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    17
    4
    2
    Vision blurred
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    3
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    3
    1
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 50 (10.00%)
    9 / 51 (17.65%)
    9 / 50 (18.00%)
    4 / 32 (12.50%)
         occurrences all number
    8
    18
    12
    5
    Abdominal pain upper
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 51 (9.80%)
    9 / 50 (18.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    6
    11
    1
    Constipation
         subjects affected / exposed
    12 / 50 (24.00%)
    6 / 51 (11.76%)
    13 / 50 (26.00%)
    1 / 32 (3.13%)
         occurrences all number
    20
    6
    18
    1
    Diarrhoea
         subjects affected / exposed
    28 / 50 (56.00%)
    35 / 51 (68.63%)
    36 / 50 (72.00%)
    7 / 32 (21.88%)
         occurrences all number
    71
    110
    135
    12
    Dry mouth
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 51 (3.92%)
    4 / 50 (8.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    2
    5
    0
    Dyspepsia
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 51 (9.80%)
    5 / 50 (10.00%)
    2 / 32 (6.25%)
         occurrences all number
    6
    5
    18
    2
    Flatulence
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 51 (1.96%)
    5 / 50 (10.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    4
    6
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 51 (3.92%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences all number
    4
    5
    2
    1
    Haemorrhoids
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 51 (1.96%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences all number
    4
    1
    3
    1
    Nausea
         subjects affected / exposed
    11 / 50 (22.00%)
    16 / 51 (31.37%)
    15 / 50 (30.00%)
    3 / 32 (9.38%)
         occurrences all number
    15
    29
    26
    5
    Stomatitis
         subjects affected / exposed
    8 / 50 (16.00%)
    7 / 51 (13.73%)
    10 / 50 (20.00%)
    0 / 32 (0.00%)
         occurrences all number
    12
    8
    13
    0
    Vomiting
         subjects affected / exposed
    9 / 50 (18.00%)
    9 / 51 (17.65%)
    10 / 50 (20.00%)
    2 / 32 (6.25%)
         occurrences all number
    12
    15
    32
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 51 (13.73%)
    8 / 50 (16.00%)
    1 / 32 (3.13%)
         occurrences all number
    6
    16
    22
    2
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    2
    0
    0
    3
    Alopecia
         subjects affected / exposed
    25 / 50 (50.00%)
    23 / 51 (45.10%)
    25 / 50 (50.00%)
    3 / 32 (9.38%)
         occurrences all number
    38
    30
    29
    3
    Blister
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    13
    3
    0
    1
    Dry skin
         subjects affected / exposed
    9 / 50 (18.00%)
    12 / 51 (23.53%)
    12 / 50 (24.00%)
    0 / 32 (0.00%)
         occurrences all number
    12
    14
    24
    0
    Erythema
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 51 (7.84%)
    7 / 50 (14.00%)
    1 / 32 (3.13%)
         occurrences all number
    8
    7
    11
    1
    Hair texture abnormal
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    5 / 50 (10.00%)
    1 / 32 (3.13%)
         occurrences all number
    4
    13
    6
    1
    Nail disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    1
    2
    Pain of skin
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 51 (13.73%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    7
    3
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    26 / 50 (52.00%)
    23 / 51 (45.10%)
    27 / 50 (54.00%)
    4 / 32 (12.50%)
         occurrences all number
    72
    88
    78
    11
    Pruritus
         subjects affected / exposed
    12 / 50 (24.00%)
    13 / 51 (25.49%)
    13 / 50 (26.00%)
    0 / 32 (0.00%)
         occurrences all number
    18
    19
    17
    0
    Rash
         subjects affected / exposed
    15 / 50 (30.00%)
    16 / 51 (31.37%)
    16 / 50 (32.00%)
    1 / 32 (3.13%)
         occurrences all number
    28
    30
    29
    2
    Rash erythematous
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Rash generalised
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    5
    3
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    6
    1
    1
    0
    Skin exfoliation
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 51 (5.88%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    4
    8
    0
    Skin lesion
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 51 (7.84%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    8
    4
    1
    Skin toxicity
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 51 (9.80%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    13
    7
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 50 (22.00%)
    5 / 51 (9.80%)
    8 / 50 (16.00%)
    3 / 32 (9.38%)
         occurrences all number
    16
    6
    13
    5
    Back pain
         subjects affected / exposed
    6 / 50 (12.00%)
    7 / 51 (13.73%)
    9 / 50 (18.00%)
    3 / 32 (9.38%)
         occurrences all number
    8
    10
    12
    5
    Bone pain
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 51 (1.96%)
    4 / 50 (8.00%)
    2 / 32 (6.25%)
         occurrences all number
    4
    1
    10
    3
    Flank pain
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 51 (7.84%)
    2 / 50 (4.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    7
    2
    0
    Muscular weakness
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    8
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 50 (10.00%)
    6 / 51 (11.76%)
    3 / 50 (6.00%)
    3 / 32 (9.38%)
         occurrences all number
    5
    10
    3
    3
    Musculoskeletal pain
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 51 (9.80%)
    8 / 50 (16.00%)
    0 / 32 (0.00%)
         occurrences all number
    7
    5
    12
    0
    Myalgia
         subjects affected / exposed
    6 / 50 (12.00%)
    7 / 51 (13.73%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    6
    10
    2
    0
    Neck pain
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Pain in extremity
         subjects affected / exposed
    9 / 50 (18.00%)
    8 / 51 (15.69%)
    11 / 50 (22.00%)
    3 / 32 (9.38%)
         occurrences all number
    25
    10
    25
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 51 (7.84%)
    5 / 50 (10.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    6
    5
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 50 (22.00%)
    13 / 51 (25.49%)
    20 / 50 (40.00%)
    5 / 32 (15.63%)
         occurrences all number
    13
    17
    31
    5
    Dehydration
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 51 (5.88%)
    4 / 50 (8.00%)
    1 / 32 (3.13%)
         occurrences all number
    4
    5
    4
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    4
    3
    3
    Hyperuricaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 51 (1.96%)
    4 / 50 (8.00%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    8
    5
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    9
    3
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 51 (11.76%)
    5 / 50 (10.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    10
    6
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 51 (7.84%)
    2 / 50 (4.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    9
    3
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 51 (7.84%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences all number
    4
    5
    1
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    4 / 50 (8.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    2
    5
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 51 (7.84%)
    4 / 50 (8.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    10
    6
    0
    Rhinitis
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    4
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences all number
    3
    5
    3
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
    1 / 50 (2.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    5
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2007
    • The informed consent template: − In the Safety section: listed in detail the expected adverse events for sorafenib. − In the Alternative Therapy section: listed the alternative therapies available instead of indicating that the subject’s doctor will discuss them. • Clarified the fasting requirements for sorafenib administration. • The wording on the storage conditions for sorafenib in the Pharmacy Guide (Appendix C) was revised to improve the consistency with the approved sorafenib label. • The confidentiality language in the pharmacogenetic consent was updated.
    13 Aug 2008
    • Updated Informed Consent and Introduction • Clarified unblinding details • Updated and clarified inclusion/exclusion criteria (serum creatinine, hemostatic function, prior malignancies, concurrent anticoagulation therapy, surgical procedures, pancreatitis) • Revised the sorafenib toxicity management instructions to allow for potential re-escalation of the sorafenib dose, at the investigator’s discretion, in subjects who had undergone a dose reduction due to skin toxicity • Added requirement for all non-serious and serious adverse events to be collected from the time subjects signed the informed consent • Revised AMG 386/placebo pharmacokinetic and immunogenicity sample collection time points • Removed requirement that post-dose ECGs be performed in triplicate • Clarified that all ECG reports were to include the heart rate and QRS, QT, QTc, RR and PR intervals • Clarified time frames for screening safety laboratory assessments and radiological imaging • Required that baseline samples for immunogenicity, biomarker, and pharmacokinetic assessments be taken before infusion • Removed PRO Questionnaires from the screening procedures • Clarified the definition of cycles • Clarified how the dose of AMG 386 was to be calculated • Clarified that long-term follow-up radiographic assessment for subjects who discontinued treatment before disease progression would stop if subjects commence new therapy • Revised the hypothesis statement • Clarified on which CRFs deaths were to be reported and how signs and symptoms of disease progression were to be reported • Reduced the analyses performed on data subsets that were not deemed useful or relevant in this subject population • Included pairwise comparisons between treatment arms for data subsets of interest and removed closed testing procedures throughout the statistical analysis section • Added language encouraging sites to repeat confirmatory scans within 28 to 35 days after initial observation of a P

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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