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    Clinical Trial Results:
    Phase 2 Open-label Multicenter Study to Evaluate the Safety and Efficacy of Sunitinib Malate in Combination With AMG 386 as First Line or Second Line Therapy for Subjects With Metastatic Renal Cell Carcinoma

    Summary
    EudraCT number
    		 2008-006210-14
    Trial protocol
    		 BE   FR  
    Global end of trial date
    25 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2020
    First version publication date
    25 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20080579
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00853372
    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
    25 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safety and tolerability of trebananib in combination with sunitinib in subjects with metastatic renal cell carcinoma (mRCC).
    Protection of trial subjects
    This study was conducted in accordance with United States Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312, and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Before a subject could enter study or any study-specific procedures could be performed, the investigator was required to obtain written informed consent from the subject or legally acceptable representative after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. A separate informed consent form was required if a subject was to participate in the optional pharmacogenetics portion of the study.
    Background therapy
    		 Sunitinib (SUTENT [oral multi-kinase inhibitor]) was administered 50 mg QD and was considered to be the background therapy as it is licensed for treatment of RCC and was administered to all subjects.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Poland: 22
    Worldwide total number of subjects
    85
    EEA total number of subjects
    59
    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)
    57
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 18 sites in the United States, Australia, Belgium, France, and Poland. The first participant was enrolled on 28 May 2009. The last participant was enrolled on 29 November 2010.

    Pre-assignment
    Screening details
    		 All participants had screening procedures completed within 28 days prior to enrollment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trebananib 10 mg/kg + Sunitinib
    Arm description
    		 Trebananib 10 mg/kg intravenously (IV) once weekly (QW) plus sunitinib 50 mg orally (PO) once daily (QD) 4 weeks on/2 weeks off
    Arm type
    		 Experimental

    Investigational medicinal product name
    trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Angiogenesis inhibitor
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment with trebananib was to continue until disease progression, clinical progression, unacceptable toxicity, withdrawal of consent, or death.

    Arm title
    		 Trebananib 15 mg/kg + Sunitinib
    Arm description
    		 Trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off
    Arm type
    		 Experimental

    Investigational medicinal product name
    trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Angiogenesis inhibitor
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment with trebananib was to continue until disease progression, clinical progression, unacceptable toxicity, withdrawal of consent, or death.

    Number of subjects in period 1
    		Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Started
    43
    42
    Completed
    11
    13
    Not completed
    32
    29
         Adverse event, serious fatal
    30
    26
         Full Consent Withdrawn
    1
    1
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trebananib 10 mg/kg + Sunitinib
    Reporting group description
    		 Trebananib 10 mg/kg intravenously (IV) once weekly (QW) plus sunitinib 50 mg orally (PO) once daily (QD) 4 weeks on/2 weeks off

    Reporting group title
    Trebananib 15 mg/kg + Sunitinib
    Reporting group description
    		 Trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off

    Reporting group values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib Total
    Number of subjects
    		 43 42 85
    Age Categorical
    Units: participants
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.3 ( 9.7 ) 61.4 ( 8.5 ) -
    Sex: Female, Male
    Units:
        Female
    		 5 10 15
        Male
    		 38 32 70
    Race/Ethnicity, Customized
    Units: Subjects
        White or Caucasian
    		 41 42 83
        Black or African American
    		 1 0 1
        Hispanic or Latino
    		 1 0 1
        Asian
    		 0 0 0
        Japanese
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Aborigine
    		 0 0 0
        Other, Not Specified
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Trebananib 10 mg/kg + Sunitinib
    Reporting group description
    		 Trebananib 10 mg/kg intravenously (IV) once weekly (QW) plus sunitinib 50 mg orally (PO) once daily (QD) 4 weeks on/2 weeks off

    Reporting group title
    Trebananib 15 mg/kg + Sunitinib
    Reporting group description
    		 Trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off

    Primary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations (DCs) Due to Adverse Events (AEs)

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations (DCs) Due to Adverse Events (AEs) [1]
    End point description
    AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: an AE that: is fatal; is life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an other significant medical hazard. Treatment-emergent AEs (TEAEs) are those that occurred after the first administration of study drug through 30 days after the last study drug administration. Severity was graded according to Common Terminology Criteria (CTCAE) version 3.0, as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib.
    End point type
    Primary
    End point timeframe
    From first dose of study drug to 30 days after last dose. Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib.
    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: Descriptive statistics are presented per protocol.
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    42
    Units: participants
        TEAEs, All
    43
    42
        TEAEs, Grade ≥ 3
    32
    34
        TEAEs, Grade ≥ 4
    4
    7
        TEAEs, Fatal AEs
    1
    1
        TEAEs, SAEs
    17
    26
        TEAEs Leading to (→) DC of Trebananib
    7
    14
        TEAEs → DC of Trebananib, Serious
    5
    12
        TEAEs → DC of Trebananib, Non-Serious
    2
    2
        TEAEs → DC of Sunitinib
    9
    16
        TEAEs → DC of Sunitinib, Serious
    5
    12
        TEAEs → DC of Sunitinib, Non-Serious
    4
    5
        TEAEs → DC of All Treatment
    6
    14
        TEAEs → DC of All Treatment, Serious
    5
    12
        TEAEs → DC of All Treatment, Non-Serious
    1
    2
        Treatment-Related (TR) TEAEs, All
    43
    42
        TR TEAEs, Grade ≥ 3
    25
    31
        TR TEAEs, Grade ≥ 4
    2
    5
        TR TEAEs, Fatal AEs
    0
    1
        TR TEAEs, SAEs
    11
    18
        TR TEAEs → DC of Trebananib
    6
    13
        TR TEAEs → DC of Trebananib, Serious
    4
    11
        TR TEAEs → DC of Trebananib, Non-Serious
    2
    2
        TR TEAEs → DC of Sunitinib
    8
    15
        TR TEAEs → DC of Sunitinib, Serious
    4
    11
        TR TEAEs → DC of Sunitinib, Non-Serious
    4
    5
        TR TEAEs → DC of All Treatment
    5
    13
        TR TEAEs → DC of All Treatment, Serious
    4
    11
        TR TEAEs → DC of All Treatment, Non-Serious
    1
    2
        Trebananib-Related (TrR) TEAEs, All
    34
    39
        TrR TEAEs, Grade ≥ 3
    17
    19
        TrR TEAEs, Grade ≥ 4
    1
    4
        TrR TEAEs, Fatal AEs
    0
    1
        TrR TEAEs, SAEs
    10
    15
        TrR TEAEs → DC of Trebananib
    6
    13
        TrR TEAEs → DC of Trebananib, Serious
    4
    11
        TrR TEAEs → DC of Trebananib, Non-Serious
    2
    2
        TrR TEAEs → DC of Sunitinib
    6
    13
        TrR TEAEs → DC of Sunitinib, Serious
    4
    11
        TrR TEAEs → DC of Sunitinib, Non-Serious
    2
    3
        TrR TEAEs → DC of All Treatment
    5
    13
        TrR TEAEs → DC of All Treatment, Serious
    4
    11
        TrR TEAEs → DC of All Treatment, Non-Serious
    1
    2
        Sunitinib-Related (SR) TEAEs, All
    43
    42
        SR TEAEs, Grade ≥ 3
    25
    31
        SR TEAEs, Grade ≥ 4
    2
    5
        SR TEAEs, Fatal AEs
    0
    1
        SR TEAEs, SAEs
    9
    15
        SR TEAEs → DC of Trebananib
    4
    11
        SR TEAEs → DC of Trebananib, Serious
    3
    10
        SR TEAEs → DC of Trebananib, Non-Serious
    1
    1
        SR TEAEs → DC Sunitinib
    7
    13
        SR TEAEs → DC of Sunitinib, Serious
    3
    10
        SR TEAEs → DC of Sunitinib, Non-Serious
    4
    4
        SR TEAEs → DC of All Treatment
    4
    11
        SR TEAEs → DC of All Treatment, Serious
    3
    10
        SR TEAEs → DC of All Treatment, Non-Serious
    1
    1
    No statistical analyses for this end point

    Primary: Number of Participants With Dose Delays Due to Adverse Events

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    End point title
    		 Number of Participants With Dose Delays Due to Adverse Events [2]
    End point description
    A trebananib dose was considered delayed if it was administered 11 or more days from the previous trebananib infusion. A sunitinib dose was considered delayed if it was administered 3 or more days from the previous dose, except during holidays. Safety Analysis Set: participants who received at least 1 dose of trebananib and 1 dose of sunitinib.
    End point type
    Primary
    End point timeframe
    Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib.
    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: Descriptive statistics are presented per protocol.
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    42
    Units: participants
        Trebananib dose delays
    26
    28
        Sunitinib dose delays
    29
    27
    No statistical analyses for this end point

    Primary: Number of Participants With Sunitinib Dose Modifications Within 12 Weeks of First Dose

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    End point title
    		 Number of Participants With Sunitinib Dose Modifications Within 12 Weeks of First Dose [3]
    End point description
    Participants who had a sunitinib dose modification within 12 weeks from their first dose due to adverse event, laboratory toxicity, or laboratory toxicity and adverse event. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib.
    End point type
    Primary
    End point timeframe
    first 12 weeks of study treatment
    Notes
    [3] - 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: Descriptive statistics are presented per protocol.
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    42
    Units: participants
        Any Dose Modification (DM)
    25
    24
        DM Due to Adverse Event
    20
    18
        DM Due to Laboratory Toxicity
    4
    4
        DM Due to Laboratory Toxicity and Adverse Event
    1
    2
    No statistical analyses for this end point

    Primary: Number of Participants With Worst Post-Baseline Grade 3 or Higher Toxicity in Laboratory Values

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    End point title
    		 Number of Participants With Worst Post-Baseline Grade 3 or Higher Toxicity in Laboratory Values [4]
    End point description
    Severity was graded according to Common Terminology Criteria (CTCAE) version 3.0, as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib.
    End point type
    Primary
    End point timeframe
    From first dose of study drug to 30 days after last dose. Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented per protocol.
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    42
    Units: participants
        Alanine Aminotransferase, Above Normal (AN)
    3
    2
        Albumin, Below Normal (BN)
    1
    1
        Alkaline Phosphatase, AN
    0
    2
        Amylase, AN
    2
    5
        Aspartate Aminotransferase, AN
    2
    2
        Glucose, AN
    1
    3
        Glucose, BN
    1
    0
        Lipase, AN
    5
    7
        Magnesium, BN
    0
    1
        Phosphorus, BN
    3
    4
        Potassium, BN
    2
    2
        Sodium, BN
    1
    4
        Total Bilirubin, AN
    0
    2
        Absolute Neutrophil Count, BN
    3
    5
        Hemoglobin, BN
    1
    3
        Lymphocytes, BN
    6
    3
        Partial Thromboplastin Time, AN
    1
    1
        Platelets, BN
    3
    2
        Total Neutrophils, BN
    3
    5
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) per modified Response Evaluation Criteria in Solid Tumor (RECIST) criteria (responder). A confirmed CR requires 2 consecutive assessments of CR at least 28 days apart. A confirmed PR requires 2 consecutive assessments at least 28 days apart of PR or CR. All participants who did not meet the criteria for an objective response by the analysis cutoff date were considered non responders. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib. Participants with baseline measureable disease.
    End point type
    Secondary
    End point timeframe
    48 months after last subject enrolled (LSE)
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    41
    Units: percentage of participants
        number (confidence interval 80%)
    58.1 (47.2 to 68.5)
    63.4 (52.2 to 73.6)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate: Duration of Response (DOR)

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    End point title
    		 Kaplan-Meier Estimate: Duration of Response (DOR)
    End point description
    DOR was calculated as the time from the first confirmed objective response to first observed disease progression per modified RECIST v. 1.0 criteria or death due to any cause. DOR was calculated only for participants who had an objective response. Objective response was defined as either a confirmed CR or PR per modified RECIST criteria. A confirmed CR required 2 consecutive assessments of CR at least 28 days apart. A confirmed PR required 2 consecutive assessments at least 28 days apart of PR or CR. Participants not meeting criteria for progression by the analysis data cutoff date were censored at their last evaluable radiographical disease assessment date. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib. Participants with an objective response.
    End point type
    Secondary
    End point timeframe
    48 months after LSE
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    25
    26
    Units: months
        median (confidence interval 80%)
    18.0 (11.8 to 24.4)
    18.4 (11.5 to 24.8)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR was defined as the percentage of participants with confirmed CR or PR or stable disease (SD), as defined by modified RECIST v1.0 criteria. A confirmed CR required 2 consecutive assessments of CR at least 28 days apart. A confirmed PR requires 2 consecutive assessments at least 28 days apart of PR or CR. CR or PR was confirmed at least 28 days after the criteria for response were first met. A response assessment of PR or CR that was not subsequently confirmed at least 4 weeks later were included as SD.
    End point type
    Secondary
    End point timeframe
    48 months after LSE
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    41
    Units: percentage of participants
        number (confidence interval 80%)
    72.1 (61.5 to 81.0)
    75.6 (64.9 to 84.3)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate: Progression Free Survival (PFS)

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    End point title
    		 Kaplan-Meier Estimate: Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from enrollment date to date of disease progression (ie, radiographic progression) per modified RECIST v 1.0 criteria or death. Radiological imaging to assess disease status was performed until participants developed disease progression. Events of radiographic progression per modified RECIST 1.0 that occurred after initiation of subsequent anticancer therapy were not considered PFS events. Deaths occurring after initiation of subsequent anticancer therapy were considered PFS events. Participants not meeting criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib.
    End point type
    Secondary
    End point timeframe
    48 months after LSE
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    42
    Units: months
        median (confidence interval 80%)
    13.9 (11.0 to 16.1)
    16.5 (13.3 to 21.4)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate: Overall Survival (OS)

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    End point title
    		 Kaplan-Meier Estimate: Overall Survival (OS)
    End point description
    The time from enrollment date to date of death. Participants who had not died by the analysis data cutoff date were censored at their last contact date. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib.
    End point type
    Secondary
    End point timeframe
    48 months after LSE
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    43
    42
    Units: months
        median (confidence interval 80%)
    36.0 (26.0 to 52.9)
    38.7 (31.5 to 42.6)
    No statistical analyses for this end point

    Secondary: Maximum Percent Reduction From Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions From Baseline to Post-Baseline Nadir

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    End point title
    		 Maximum Percent Reduction From Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions From Baseline to Post-Baseline Nadir
    End point description
    Change in tumor burden was evaluated by the maximum percent reduction from baseline in the SLD of target lesions. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib. Participants with baseline measureable disease and non-missing baseline and post-baseline data.
    End point type
    Secondary
    End point timeframe
    Baseline, 48 months after LSE
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    41
    40
    Units: percent reduction in SLD
        arithmetic mean (confidence interval 80%)
    -36.0 (-43.4 to -28.6)
    -41.8 (-48.4 to -35.3)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: Maximum Observed Concentration (Cmax) for Trebananib Over Time

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    End point title
    		 Pharmacokinetic Parameter: Maximum Observed Concentration (Cmax) for Trebananib Over Time
    End point description
    Pharmacokinetics Analysis Set: participants with evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Pre-infusion and up to 10 minutes post-infusion on Weeks 1, 4, 7, 10, 13, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug)
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    38 [5]
    41 [6]
    Units: µg/mL
    median (full range (min-max))
        Week 1; n=38, 41
    222 (63.2 to 819)
    297 (152 to 535)
        Week 4; n=32, 22
    285 (82.4 to 574)
    377 (258 to 647)
        Week 7; n=32, 28
    260 (75.3 to 550)
    377 (238 to 1830)
        Week 10; n=32, 23
    257 (105 to 630)
    476 (184 to 770)
        Week 13; n=26, 22
    219 (105 to 390)
    385 (216 to 785)
        Week 22; n=31, 23
    249 (92.8 to 385)
    417 (224 to 758)
        Week 34; n=24, 18
    240 (137 to 628)
    387 (77.7 to 571)
        Week 46; n=19, 7
    221 (159 to 700)
    349 (235 to 908)
        Week 58; n=13, 0
    229 (158 to 606)
    99999 (99999 to 99999)
        Week 70; n=15, 0
    185 (108 to 362)
    99999 (99999 to 99999)
        Week 82; n=15, 0
    223 (94.1 to 272)
    99999 (99999 to 99999)
        Week 94; n=2, 0
    270 (173 to 367)
    99999 (99999 to 99999)
        Week 106; n=1, 0
    289 (289 to 289)
    99999 (99999 to 99999)
        Safety Follow-Up; n=11, 3
    3.46 (1.26 to 6.16)
    8.26 (5.62 to 11.8)
    Notes
    [5] - n=participants with an assessment at given time point.
    [6] - n=participants with an assessment at given time point. 99999=not applicable (NA; n=0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: Minimum Observed Concentration (Cmin) for Trebananib Over Time

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    End point title
    		 Pharmacokinetic Parameter: Minimum Observed Concentration (Cmin) for Trebananib Over Time
    End point description
    Pharmacokinetics Analysis Set: participants with evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Weeks 4, 7, 10, 13, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug)
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    38 [7]
    29 [8]
    Units: µg/mL
    median (full range (min-max))
        Week 4; n=38, 29
    20.4 (6.22 to 41.9)
    27.3 (6.35 to 95.4)
        Week 7; n=35, 29
    30.1 (12.2 to 75.9)
    42.0 (14.9 to 90.4)
        Week 10; n=33, 23
    23.3 (9.09 to 72.3)
    32.2 (13.9 to 85.6)
        Week 13; n=33, 25
    26.1 (8.54 to 73.8)
    43.2 (15.1 to 99.5)
        Week 22; n=32, 24
    19.9 (8.59 to 63.1)
    46.2 (16.2 to 73.7)
        Week 34; n=23, 18
    24.1 (9.88 to 66.2)
    35.9 (15.3 to 79.2)
        Week 46; n=21, 8
    23.2 (6.46 to 64.4)
    30.5 (21.0 to 71.8)
        Week 58; n=15, 0
    27.9 (8.61 to 43.3)
    99999 (99999 to 99999)
        Week 70; n=15, 0
    26.2 (10.5 to 35.9)
    99999 (99999 to 99999)
        Week 82; n=5, 0
    22.5 (17.9 to 33.0)
    99999 (99999 to 99999)
        Week 94; n=2, 0
    25.9 (19.9 to 31.8)
    99999 (99999 to 99999)
        Week 106; n=1, 0
    19.3 (19.3 to 19.3)
    99999 (99999 to 99999)
        Safety Follow-Up; n=11, 3
    3.46 (1.26 to 6.16)
    8.26 (5.62 to 11.8)
    Notes
    [7] - n=participants with an assessment at given time point.
    [8] - n=participants with an assessment at given time point. 99999=not applicable (n=0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: Cmin for Sunitinib Over Time

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    End point title
    		 Pharmacokinetic Parameter: Cmin for Sunitinib Over Time
    End point description
    Pharmacokinetics Analysis Set: participants with evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Weeks 4, 7, 10, 16, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug)
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    9 [9]
    7 [10]
    Units: ng/mL
    median (full range (min-max))
        Week 4; n=6, 6
    58.6 (41.1 to 124)
    70.6 (50.8 to 105)
        Week 7; n=9, 7
    0.763 (-99999 to 4.68)
    1.65 (-99999 to 3.78)
        Week 10; n=9, 5
    66.1 (46.7 to 136)
    64.7 (42.4 to 95.4)
        Week 16; n=5, 3
    65.8 (47.1 to 91.9)
    73.1 (49.1 to 92.7)
        Week 22; n=5, 1
    49.0 (33.3 to 97.1)
    41.2 (41.2 to 41.2)
        Week 34; n=4, 1
    50.2 (-99999 to 110)
    34.8 (34.8 to 34.8)
        Week 46; n=3, 2
    59.5 (49.4 to 66.4)
    33.5 (23.3 to 43.7)
        Week 58; n=2, 0
    87.0 (51.9 to 122)
    99999 (99999 to 99999)
        Week 70; n=1, 0
    56.4 (56.4 to 56.4)
    99999 (99999 to 99999)
        Week 82; n=1, 0
    65.9 (65.9 to 65.9)
    99999 (99999 to 99999)
        Week 94; n=1, 0
    64.2 (64.2 to 64.2)
    99999 (99999 to 99999)
        Week 106; n=1, 0
    83.5 (83.5 to 83.5)
    99999 (99999 to 99999)
        Safety Follow-Up; n=6, 0
    -99999 (-99999 to 2.14)
    99999 (99999 to 99999)
    Notes
    [9] - n=participants with assessment at given time point. -99999: < lower limit of quantification (LLOQ)
    [10] - n=participants with assessment at given time point. 99999: NA (n=0); -99999: < LLOQ
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: Cmin for Sunitinib Metabolite Over Time

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    End point title
    		 Pharmacokinetic Parameter: Cmin for Sunitinib Metabolite Over Time
    End point description
    Pharmacokinetics Analysis Set: participants with evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Weeks 4, 7, 10, 16, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug)
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    9 [11]
    7 [12]
    Units: ng/mL
    median (full range (min-max))
        Week 4; n=6, 6
    22.8 (11.6 to 29.4)
    29.2 (16.5 to 43.4)
        Week 7; n=9, 7
    1.21 (0.582 to 3.89)
    1.71 (0.405 to 3.22)
        Week 10; n=9, 5
    19.2 (14.0 to 40.6)
    21.5 (18.0 to 41.3)
        Week 16; n=5, 3
    19.3 (13.7 to 22.7)
    22.0 (21.6 to 40.5)
        Week 22; n=5, 1
    12.7 (10.1 to 28.5)
    18.7 (18.7 to 18.7)
        Week 34; n=4, 1
    18.3 (-99999 to 38.3)
    15.0 (15.0 to 15.0)
        Week 46; n=3, 2
    15.0 (10.3 to 23.1)
    10.6 (7.87 to 13.4)
        Week 58; n=2, 0
    25.7 (20.1 to 31.2)
    99999 (99999 to 99999)
        Week 70; n=1, 0
    22.4 (22.4 to 22.4)
    99999 (99999 to 99999)
        Week 82; n=1, 0
    25.4 (25.4 to 25.4)
    99999 (99999 to 99999)
        Week 94; n=1, 0
    22.1 (22.1 to 22.1)
    99999 (99999 to 99999)
        Week 106; n=1, 0
    32.4 (32.4 to 32.4)
    99999 (99999 to 99999)
        Safety Follow-Up; n=6, 0
    0.138 (-99999 to 1.15)
    99999 (99999 to 99999)
    Notes
    [11] - n=participants with assessment at given time point. -99999: < LLOQ
    [12] - n=participants with assessment at given time point.99999=NA (n=0); -99999: < LLOQ
    No statistical analyses for this end point

    Secondary: Number of Participants Binding Antibody- or Neutralizing Antibody-Positive Post-Baseline

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    End point title
    		 Number of Participants Binding Antibody- or Neutralizing Antibody-Positive Post-Baseline
    End point description
    Transient positive results were defined as a positive post-baseline result followed by a negative result at the participant's last time point tested within the study period. Safety Analysis Set: all participants who received at least 1 dose of trebananib and 1 dose of sunitinib. Participants with a post-baseline result and a negative result or no result at baseline.
    End point type
    Secondary
    End point timeframe
    48 months after LSE
    End point values
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Number of subjects analysed
    41
    41
    Units: participants
        Binding Antibody Positive Post-Baseline (PBL)
    0
    0
        Binding Antibody Positive PBL, Transient
    0
    0
        Neutralizing Antibody Positive PBL
    0
    0
        Neutralizing Antibody Positive PBL, Transient
    0
    0
    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 to 30 days after last dose. Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Trebananib 10 mg/kg + Sunitinib
    Reporting group description
    		 Trebananib 10 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off

    Reporting group title
    Trebananib 15 mg/kg + Sunitinib
    Reporting group description
    		 Trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off

    Serious adverse events
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 43 (39.53%)
    26 / 42 (61.90%)
         number of deaths (all causes)
    30
    26
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cancer
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site inflammation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain hypoxia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectourethral fistula
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trebananib 10 mg/kg + Sunitinib Trebananib 15 mg/kg + Sunitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 43 (100.00%)
    42 / 42 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 43 (60.47%)
    23 / 42 (54.76%)
         occurrences all number
    61
    60
    Hypotension
         subjects affected / exposed
    3 / 43 (6.98%)
    7 / 42 (16.67%)
         occurrences all number
    5
    10
    Pallor
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 43 (37.21%)
    20 / 42 (47.62%)
         occurrences all number
    60
    66
    Catheter site pain
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 42 (11.90%)
         occurrences all number
    1
    6
    Chills
         subjects affected / exposed
    3 / 43 (6.98%)
    6 / 42 (14.29%)
         occurrences all number
    3
    6
    Face oedema
         subjects affected / exposed
    15 / 43 (34.88%)
    21 / 42 (50.00%)
         occurrences all number
    50
    50
    Fatigue
         subjects affected / exposed
    16 / 43 (37.21%)
    14 / 42 (33.33%)
         occurrences all number
    40
    50
    Generalised oedema
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 42 (7.14%)
         occurrences all number
    6
    7
    Influenza like illness
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 42 (7.14%)
         occurrences all number
    7
    3
    Localised oedema
         subjects affected / exposed
    6 / 43 (13.95%)
    3 / 42 (7.14%)
         occurrences all number
    8
    3
    Malaise
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    11
    1
    Mucosal dryness
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Mucosal inflammation
         subjects affected / exposed
    22 / 43 (51.16%)
    25 / 42 (59.52%)
         occurrences all number
    51
    51
    Oedema peripheral
         subjects affected / exposed
    24 / 43 (55.81%)
    24 / 42 (57.14%)
         occurrences all number
    59
    65
    Pyrexia
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 42 (7.14%)
         occurrences all number
    4
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 43 (30.23%)
    12 / 42 (28.57%)
         occurrences all number
    29
    17
    Dysphonia
         subjects affected / exposed
    7 / 43 (16.28%)
    2 / 42 (4.76%)
         occurrences all number
    8
    2
    Dyspnoea
         subjects affected / exposed
    7 / 43 (16.28%)
    8 / 42 (19.05%)
         occurrences all number
    7
    17
    Dyspnoea exertional
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 42 (9.52%)
         occurrences all number
    6
    5
    Epistaxis
         subjects affected / exposed
    12 / 43 (27.91%)
    6 / 42 (14.29%)
         occurrences all number
    23
    7
    Hiccups
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    Nasal dryness
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    7 / 43 (16.28%)
    5 / 42 (11.90%)
         occurrences all number
    11
    12
    Pleural effusion
         subjects affected / exposed
    5 / 43 (11.63%)
    3 / 42 (7.14%)
         occurrences all number
    7
    4
    Rhinorrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 42 (4.76%)
         occurrences all number
    5
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 42 (4.76%)
         occurrences all number
    5
    2
    Depression
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 42 (7.14%)
         occurrences all number
    4
    8
    Insomnia
         subjects affected / exposed
    8 / 43 (18.60%)
    5 / 42 (11.90%)
         occurrences all number
    11
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 42 (7.14%)
         occurrences all number
    5
    9
    Amylase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    1
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 42 (4.76%)
         occurrences all number
    4
    6
    Blood creatinine increased
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 42 (7.14%)
         occurrences all number
    3
    4
    Lipase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 42 (11.90%)
         occurrences all number
    1
    6
    Weight decreased
         subjects affected / exposed
    5 / 43 (11.63%)
    4 / 42 (9.52%)
         occurrences all number
    8
    11
    Weight increased
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    39
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 42 (0.00%)
         occurrences all number
    5
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    5 / 43 (11.63%)
    3 / 42 (7.14%)
         occurrences all number
    5
    4
    Dizziness
         subjects affected / exposed
    10 / 43 (23.26%)
    6 / 42 (14.29%)
         occurrences all number
    11
    21
    Dysgeusia
         subjects affected / exposed
    6 / 43 (13.95%)
    3 / 42 (7.14%)
         occurrences all number
    8
    4
    Formication
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    5
    1
    Headache
         subjects affected / exposed
    13 / 43 (30.23%)
    6 / 42 (14.29%)
         occurrences all number
    25
    10
    Neuropathy peripheral
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 42 (9.52%)
         occurrences all number
    4
    4
    Paraesthesia
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 42 (7.14%)
         occurrences all number
    4
    4
    Presyncope
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    6
    1
    Sciatica
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 42 (2.38%)
         occurrences all number
    3
    1
    Syncope
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    4
    3
    Taste disorder
         subjects affected / exposed
    14 / 43 (32.56%)
    10 / 42 (23.81%)
         occurrences all number
    26
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 43 (11.63%)
    7 / 42 (16.67%)
         occurrences all number
    12
    11
    Leukopenia
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 42 (7.14%)
         occurrences all number
    4
    16
    Neutropenia
         subjects affected / exposed
    5 / 43 (11.63%)
    4 / 42 (9.52%)
         occurrences all number
    13
    15
    Thrombocytopenia
         subjects affected / exposed
    14 / 43 (32.56%)
    11 / 42 (26.19%)
         occurrences all number
    23
    23
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 42 (2.38%)
         occurrences all number
    3
    1
    Tinnitus
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Vertigo
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 42 (9.52%)
         occurrences all number
    1
    4
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    10 / 43 (23.26%)
    8 / 42 (19.05%)
         occurrences all number
    47
    16
    Glaucoma
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Lacrimation increased
         subjects affected / exposed
    13 / 43 (30.23%)
    12 / 42 (28.57%)
         occurrences all number
    18
    19
    Periorbital oedema
         subjects affected / exposed
    5 / 43 (11.63%)
    8 / 42 (19.05%)
         occurrences all number
    13
    11
    Visual acuity reduced
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 42 (4.76%)
         occurrences all number
    7
    2
    Abdominal distension
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain
         subjects affected / exposed
    13 / 43 (30.23%)
    15 / 42 (35.71%)
         occurrences all number
    28
    23
    Abdominal pain upper
         subjects affected / exposed
    14 / 43 (32.56%)
    9 / 42 (21.43%)
         occurrences all number
    33
    12
    Aphthous ulcer
         subjects affected / exposed
    9 / 43 (20.93%)
    6 / 42 (14.29%)
         occurrences all number
    15
    6
    Ascites
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    Constipation
         subjects affected / exposed
    13 / 43 (30.23%)
    8 / 42 (19.05%)
         occurrences all number
    15
    11
    Diarrhoea
         subjects affected / exposed
    33 / 43 (76.74%)
    32 / 42 (76.19%)
         occurrences all number
    144
    112
    Dry mouth
         subjects affected / exposed
    6 / 43 (13.95%)
    3 / 42 (7.14%)
         occurrences all number
    9
    3
    Dyspepsia
         subjects affected / exposed
    16 / 43 (37.21%)
    10 / 42 (23.81%)
         occurrences all number
    23
    20
    Dysphagia
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 42 (11.90%)
         occurrences all number
    2
    7
    Flatulence
         subjects affected / exposed
    2 / 43 (4.65%)
    5 / 42 (11.90%)
         occurrences all number
    2
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 43 (18.60%)
    3 / 42 (7.14%)
         occurrences all number
    9
    5
    Gingival pain
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Haemorrhoids
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 42 (11.90%)
         occurrences all number
    4
    21
    Nausea
         subjects affected / exposed
    22 / 43 (51.16%)
    19 / 42 (45.24%)
         occurrences all number
    61
    48
    Oesophagitis
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    2
    5
    Stomatitis
         subjects affected / exposed
    4 / 43 (9.30%)
    8 / 42 (19.05%)
         occurrences all number
    17
    18
    Vomiting
         subjects affected / exposed
    17 / 43 (39.53%)
    13 / 42 (30.95%)
         occurrences all number
    51
    24
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    1
    9
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    18 / 43 (41.86%)
    6 / 42 (14.29%)
         occurrences all number
    26
    8
    Erythema
         subjects affected / exposed
    6 / 43 (13.95%)
    2 / 42 (4.76%)
         occurrences all number
    9
    2
    Hair colour changes
         subjects affected / exposed
    5 / 43 (11.63%)
    3 / 42 (7.14%)
         occurrences all number
    6
    3
    Hyperhidrosis
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 42 (2.38%)
         occurrences all number
    5
    5
    Hyperkeratosis
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 42 (9.52%)
         occurrences all number
    5
    5
    Nail disorder
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    21 / 43 (48.84%)
    18 / 42 (42.86%)
         occurrences all number
    91
    45
    Pruritus
         subjects affected / exposed
    5 / 43 (11.63%)
    4 / 42 (9.52%)
         occurrences all number
    8
    4
    Rash
         subjects affected / exposed
    9 / 43 (20.93%)
    9 / 42 (21.43%)
         occurrences all number
    15
    18
    Skin discolouration
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 42 (4.76%)
         occurrences all number
    4
    2
    Skin disorder
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    Skin exfoliation
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 42 (7.14%)
         occurrences all number
    5
    5
    Skin toxicity
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 42 (9.52%)
         occurrences all number
    41
    20
    Yellow skin
         subjects affected / exposed
    4 / 43 (9.30%)
    5 / 42 (11.90%)
         occurrences all number
    4
    5
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 42 (11.90%)
         occurrences all number
    3
    8
    Proteinuria
         subjects affected / exposed
    2 / 43 (4.65%)
    6 / 42 (14.29%)
         occurrences all number
    2
    13
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 43 (4.65%)
    5 / 42 (11.90%)
         occurrences all number
    2
    7
    Hypothyroidism
         subjects affected / exposed
    21 / 43 (48.84%)
    18 / 42 (42.86%)
         occurrences all number
    25
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 43 (39.53%)
    10 / 42 (23.81%)
         occurrences all number
    30
    19
    Back pain
         subjects affected / exposed
    12 / 43 (27.91%)
    5 / 42 (11.90%)
         occurrences all number
    19
    5
    Bone pain
         subjects affected / exposed
    7 / 43 (16.28%)
    4 / 42 (9.52%)
         occurrences all number
    8
    4
    Groin pain
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 42 (4.76%)
         occurrences all number
    5
    2
    Muscle spasms
         subjects affected / exposed
    6 / 43 (13.95%)
    4 / 42 (9.52%)
         occurrences all number
    12
    4
    Muscular weakness
         subjects affected / exposed
    4 / 43 (9.30%)
    5 / 42 (11.90%)
         occurrences all number
    6
    10
    Musculoskeletal pain
         subjects affected / exposed
    7 / 43 (16.28%)
    7 / 42 (16.67%)
         occurrences all number
    8
    12
    Myalgia
         subjects affected / exposed
    6 / 43 (13.95%)
    6 / 42 (14.29%)
         occurrences all number
    7
    7
    Pain in extremity
         subjects affected / exposed
    10 / 43 (23.26%)
    5 / 42 (11.90%)
         occurrences all number
    25
    10
    Spinal pain
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    Conjunctivitis
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 42 (9.52%)
         occurrences all number
    4
    4
    Cystitis
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Ear infection
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Gastroenteritis
         subjects affected / exposed
    6 / 43 (13.95%)
    1 / 42 (2.38%)
         occurrences all number
    6
    1
    Influenza
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    Laryngitis
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 42 (4.76%)
         occurrences all number
    4
    3
    Oral herpes
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 42 (4.76%)
         occurrences all number
    3
    2
    Pharyngitis
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    4
    Rhinitis
         subjects affected / exposed
    8 / 43 (18.60%)
    4 / 42 (9.52%)
         occurrences all number
    17
    6
    Sinusitis
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Tooth abscess
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 42 (4.76%)
         occurrences all number
    5
    2
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 43 (11.63%)
    7 / 42 (16.67%)
         occurrences all number
    8
    9
    Urinary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 42 (9.52%)
         occurrences all number
    1
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 43 (39.53%)
    24 / 42 (57.14%)
         occurrences all number
    47
    44
    Dehydration
         subjects affected / exposed
    5 / 43 (11.63%)
    3 / 42 (7.14%)
         occurrences all number
    6
    8
    Hyperglycaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    4
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Hypokalaemia
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 42 (7.14%)
         occurrences all number
    10
    6
    Hypophosphataemia
         subjects affected / exposed
    3 / 43 (6.98%)
    8 / 42 (19.05%)
         occurrences all number
    3
    16
    Obesity
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2009
    - Cohort B (trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD given 4 weeks on/2 weeks off) was added. - The enrollment period was extended to 10 months to facilitate the enrollment of an additional 40 subjects.
    21 Jun 2011
    - Pleural effusion and ascites are known identified risks of trebananib, and thus a new toxicity management section was added to provide guidance to participating investigators of the study. - Toxicity management for thromboembolic events, hypokalemia, and grade 3 toxicities was clarified. - The radiologic scanning frequency interval after 3 years on study was reduced to every 6 months. - Guidelines for proscribed medications were added including immune modulators, CYP3A4 strong inducers and inhibitors, and amiodarone as excluded medications during the study. The use of low dose warfarin (≤ 1 mg PO QD) or low molecular weight heparin for prophylaxis against thrombosis was disallowed. - The Cox regression model estimation of PFS hazard rate was removed.
    24 Nov 2012
    - Serious adverse events occurring after conclusion of the study AND thought to be possibly related to investigational product were to be collected and recorded in the subject's medical record, and reported to Amgen within 1 working day of discovery or notification of the event. - The process for determination of expectedness of clinical trial adverse events for the purpose of expedited reporting to regulatory agencies globally was amended. - The Pregnancy and Lactation Reporting section was updated, and a new lactation notification worksheet was added

    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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