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    Clinical Trial Results:
    Profile of soluble and cellular biomarkers and of functional imaging during antiangiogenic therapies in cancer patients

    Summary
    EudraCT number
    		 2008-008852-18
    Trial protocol
    		 AT  
    Global end of trial date
    04 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Oct 2020
    First version publication date
    17 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PRAEMARKERAAT08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01507740
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Innsbruck
    Sponsor organisation address
    Christoph-Probst-Platz 1, Innrain 52 A, Innsbruck, Austria, 6020
    Public contact
    Priv.Doz. Dr. Andreas Pircher, Medical University Innsbruck, University Hospital for Internal Medicine V, +43 (0)512/ 504-24003,
    Scientific contact
    Priv.Doz. Dr. Andreas Pircher, Medical University Innsbruck, University Hospital for Internal Medicine V, +43 (0)512/ 504-24003,
    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
    04 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Biomarker evaluation under antiannagiogenic therapy with Nexavar, Sutent and Avastin. Eligible patients are suffering from hepatocellular carcinoma, non small cell lung cancer, renal cell cancer and colorectal cancer routinely treated with the abov mentioned antiangiogenic agents.
    Protection of trial subjects
    Laboratory examinations were part of the routine blood sampling and CT scans were performed as depended by clinical requirements. Functional imaging with dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was preplanned at study inclusion and at the time point of disease progression.
    Background therapy
    		 NSCLC patients were treated with bevacizumab monotherapy (maintenance therapy), RCC patients were treated either with sorafenib or sunitinib monotherapy, HCC patients were treated with sorafenib monotherapy.
    Evidence for comparator
    		 No comparators have been used in this trial.
    Actual start date of recruitment
    26 Oct 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
    Austria: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    9
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between November 2009 and July 2012 22 patients were included in this academic non-interventional pilot study. Patients with HCC (hepatocellular cancer), RCC (renal cell cancer) and NSCLC (non-small cell lung cancer) treated either with sorafenib, sunitinib or bevacizumab were eligible.

    Pre-assignment
    Screening details
    		 An already ongoing antiangiogenic therapy was required for study inclusion (baseline analysis). Only patients with confirmed benefit (disease stabilization) from antiangiogenic could be included, while primary resistant patients were not part of the study.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment group
    Arm description
    		 2 NSCLC patients were treated with bevacizumab monotherapy (maintenance therapy), RCC patients were treated either with sorafenib (1 patient) or sunitinib (6 patients) monotherapy,13 HCC patients were treated with sorafenib monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    H-C-687
    Other name
    Sutent
    Pharmaceutical forms
    Tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    Tablets of 50mg were given daily for 4 weeks followed by an intervall of 2 weeks with no therapy.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    2x 400mg daily

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/ kg every 3 weeks.

    Number of subjects in period 1
    		Treatment group
    Started
    22
    Completed
    22
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment goup
    Arm description
    		 During the response interval under monotherapy with antiangiogenic drugs periodical measurements at intervals of 3-7 weeks (according to local standards) were performed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    Sutent
    Pharmaceutical forms
    Tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    Tablets of 50mg were given daily for 4 weeks followed by an intervall of 2 weeks with no therapy.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    2x 400mg daily.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/ kg every 3 weeks.

    Number of subjects in period 2
    		Treatment goup
    Started
    22
    Completed
    20
    Not completed
    2
         Lost to follow-up
    2
    Period 3
    Period 3 title
    Progression
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment group
    Arm description
    		 NSCLC patients were treated with bevacizumab monotherapy (maintenance therapy), RCC patients were treated either with sorafenib or sunitinib monotherapy, HCC patients were treated with sorafenib monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    Sutent
    Pharmaceutical forms
    Tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    Tablets of 50mg were given daily for 4 weeks followed by an intervall of 2 weeks with no therapy.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    2x 400mg daily

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/ kg every 3 weeks.

    Number of subjects in period 3
    		Treatment group
    Started
    20
    Completed
    20

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 22 22
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 13 13
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65 ± 10.00 -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 18 18

    End points

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    End points reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 2 NSCLC patients were treated with bevacizumab monotherapy (maintenance therapy), RCC patients were treated either with sorafenib (1 patient) or sunitinib (6 patients) monotherapy,13 HCC patients were treated with sorafenib monotherapy.
    Reporting group title
    Treatment goup
    Reporting group description
    		 During the response interval under monotherapy with antiangiogenic drugs periodical measurements at intervals of 3-7 weeks (according to local standards) were performed.
    Reporting group title
    Treatment group
    Reporting group description
    		 NSCLC patients were treated with bevacizumab monotherapy (maintenance therapy), RCC patients were treated either with sorafenib or sunitinib monotherapy, HCC patients were treated with sorafenib monotherapy.

    Primary: TEM

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    End point title
    		 TEM
    End point description
    The aim of the present study was to generate a profile of possible mechanisms of resistance in patients with renal cell cancer (RCC), hepatocellular cancer (HCC) and non-small cell lung cancer (NSCLC) treated with sunitinib, sorafenib or bevacizumab thereby comparing and correlating changes in tumor endothelial markers (TEM) to disease progression. TEM have been shown to be selectively expressed by tumor endothelial cells and to have important biological functions (e.g. Robo4 inhibits VEGFR2 signaling). Therefore, we analyzed Robo4, Clec14 and ECSCR expression levels in PBMC, which decreased significantly at disease progression
    End point type
    Primary
    End point timeframe
    Baseline- Progression
    End point values
    		 Treatment group Treatment group
    Number of subjects analysed
    19
    19
    Units: Expression
    median (full range (min-max))
        Robo4
    1.29 (0.06 to 16.28)
    0.46 (0.12 to 5.12)
        Clec14
    1.64 (0.12 to 17.01)
    0.91 (0.06 to 21.16)
        ECSCR
    1.45 (0.04 to 18.02)
    0.57 (0.06 to 8.67)
    Statistical analysis title
    		 Robo4 expression
    Statistical analysis description
    Robo4 expression decreased significantly from baseline to disease progression.
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.04
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Clec14 expression
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.09
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 ECSCR expression
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Circulating cell populations

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    End point title
    		 Circulating cell populations
    End point description
    The aim of the present study was to generate a profile of possible mechanisms of resistance in patients with renal cell cancer (RCC), hepatocellular cancer (HCC) and non-small cell lung cancer (NSCLC) treated with sunitinib, sorafenib or bevacizumab thereby comparing and correlating changes in circulating cell populations to disease progression. Levels of CECs (circulating endothelial cells) and CEPs (circulating progenitor cells) are indicative of high vascular turnover and potential candidates for monitoring antiangiogenic therapies. Additionally CD45-CD31+ and VEGFR2+CEC cell populations were measured.
    End point type
    Primary
    End point timeframe
    Baseline- Progression
    End point values
    		 Treatment group Treatment group
    Number of subjects analysed
    17
    17
    Units: cells per milliliter
    median (full range (min-max))
        CEC
    11.88 (0.00 to 111.20)
    40.00 (13.56 to 135.40)
        CD45-CD31+
    2360 (154 to 9239)
    3021 (38 to 11535)
        CEP
    4.63 (0.00 to 27.68)
    35.44 (13.94 to 150.90)
        VEGFR2+CEC
    48.28 (7.50 to 145.80)
    13.54 (3.62 to 62.28)
    Statistical analysis title
    		 CEC level
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 CD45-CD31+ level
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.07
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 CEP level
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 VEGFR2+CEC
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Cytokine levels

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    End point title
    		 Cytokine levels
    End point description
    The aim of the present study was to generate a profile of possible mechanisms of resistance in patients with renal cell cancer (RCC), hepatocellular cancer (HCC) and non-small cell lung cancer (NSCLC) treated with sunitinib, sorafenib or bevacizumab thereby comparing and correlating changes in angiogenic growth factors to disease progression. We measured serum levels of proangiogenic cytokines at baseline and disease progression and found that VEGF, PDGF, PlGF and HGF increased during the course of therapy. In contrast, we observed that cytokines like sVEGFR2, DKK3, MIG and ICAM decreased during the course of therapy.
    End point type
    Primary
    End point timeframe
    Baseline- Progression
    End point values
    		 Treatment group Treatment group
    Number of subjects analysed
    18 [1]
    18 [2]
    Units: pg per milliliter
    median (full range (min-max))
        VEGF
    155 (53 to 381)
    189 (67 to 698)
        sVEGFR2
    179 (98 to 391)
    135 (32 to 267)
        PlGF
    4 (1 to 21)
    8 (2 to 38)
        PDGF
    656 (232 to 1034)
    690 (532 to 1146)
        DKK3
    4754 (1510 to 8758)
    4347 (1335 to 8278)
    Notes
    [1] - For PIGF 17 subjects and for PDGF 19 subjects were analysed.
    [2] - For PIGF 17 subjects and for PDGF 19 subjects were analysed.
    Statistical analysis title
    		 Serum concentration of VEGF
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.04
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Serum concentration of sVEGFR2
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.08
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Serum concentration of PIGF
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Serum concentration of PDGF
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.06
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Serum concentration of DKK3
    Comparison groups
    Treatment group v Treatment group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.08
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline- Progression
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 22 (68.18%)
    Immune system disorders
    Leukopenia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    11 / 22 (50.00%)
         occurrences all number
    11
    Stomatitis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26956051
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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