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    Clinical Trial Results:
    A PHASE II DOUBLE BLIND, RANDOMISED CONTROLLED TRIAL OF VEGF INHIBITOR AXITINIB MONOTHERAPY WITH EARLY DYNAMIC CONTRAST ENHANCED ULTRASOUND MONITORING IN CHEMOREFRACTORY THIRD LINE METASTATIC COLORECTAL CANCER- AxMUS-C

    Summary
    EudraCT number
    		 2011-002598-49
    Trial protocol
    		 GB  
    Global end of trial date
    15 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Sep 2022
    First version publication date
    08 Sep 2022
    Other versions
    Summary report(s)
    		 Final report

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO1885
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College
    Sponsor organisation address
    Du Cane Road, London, United Kingdom, W12 0HS
    Public contact
    Becky Ward, Imperial College Joint Research Office, +44 203 312 2242, becky.ward@imperial.ac.uk
    Scientific contact
    Becky Ward, Imperial College Joint Research Office, +44 203 312 2242, becky.ward@imperial.ac.uk
    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
    29 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess whether an absence of vascular (blood-supply) shutdown in the tumour, in metastatic colorectal cancer, using contrast enhanced ultrasound, in patients taking Axitinib will quickly select out patients who are not going to obtain benefit from this drug. This group of non-responsive patients should have a similar overall survival as the placebo group, whereas the patients on Axitinib who do have vascular tumour shutdown on contrast enhanced ultrasound should obtain significant benefit.
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 52
    Worldwide total number of subjects
    52
    EEA total number of subjects
    52
    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)
    38
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited in Hammersmith Hospital between 17/09/2012 and 25/07/2016

    Pre-assignment
    Screening details
    		 A total of 60 participants were screened with colorectal cancer and liver metastases were screened for eligibility, of which 52 were randomised, but one of these patients was actually a screen fail and a further 8 were considered screen failures and not randomised at all

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Randomised to axitinib or placebo in a 2:1 ratio

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Axitinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Axitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg BD increased fortnightly by a dose level up to 10mg or as tolerated - taken with food 12 hours apart

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet taken twice daily

    Arm title
    		 Screenfails
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Axitinib Placebo Screenfails
    Started
    34
    17
    1
    Completed
    34
    17
    1

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Screenfails
    Reporting group description
    		 -

    Reporting group values
    		 Axitinib Placebo Screenfails Total
    Number of subjects
    		 34 17 1 52
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 24 14 1 39
        From 65-84 years
    		 10 3 0 13
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 10 8 1 19
        Male
    		 24 9 0 33

    End points

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    End points reporting groups
    Reporting group title
    Axitinib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Screenfails
    Reporting group description
    		 -

    Subject analysis set title
    CEHPI responders
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients on axitinib who were found to have CEHPI >20% reduction at 2 weeks compared with baseline

    Subject analysis set title
    CEHPI non-responders
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who received axitinib treatment who were not found to have CEHPI >20% reduction at 2 weeks compared with baseline

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival [1]
    End point description
    End point type
    Primary
    End point timeframe
    05/09/2012 - 15/09/2018
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Screen fails (arm) were not assessed for any end point
    End point values
    		 Axitinib Placebo
    Number of subjects analysed
    32
    16
    Units: Days
        median (full range (min-max))
    111.5 (20 to 717)
    61.00 (23 to 225)
    Attachments
    		 PFS: Drug vs Placebo
    Statistical analysis title
    		 Comparison of progression-free survival curves
    Comparison groups
    Placebo v Axitinib
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0021 [2]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Survival curves are significantly different

    Primary: Progression-free survival of patients who were considered CEHPI responders at 2 weeks of treatment

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    End point title
    		 Progression-free survival of patients who were considered CEHPI responders at 2 weeks of treatment [3]
    End point description
    CEHPI is defined as the Contrast Enhanced Hepatic Perfusion Index and is a means of measuring the ratios of arterial to portal venous flow. It is assessed using ultrasound imaging. This is able to analyse differential blood flow in liver metastases that are responding and also detect differences in the distributable flow from the portal vein and hepatic artery.
    End point type
    Primary
    End point timeframe
    05/09/2012 - 15/09/2018
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only one arm was assessed for this endpoint
    End point values
    		 Axitinib CEHPI responders CEHPI non-responders
    Number of subjects analysed
    33
    14
    19
    Units: Days
        median (full range (min-max))
    123.0 (30 to 400)
    123.0 (90 to 400)
    69.0 (30 to 300)
    Attachments
    		 Axitinib Patients (CEHPI>20% Reduction at 2 weeks)
    Statistical analysis title
    		 Comparison of PFS for CEPHI Responders Vs CEPHI No
    Comparison groups
    CEHPI responders v CEHPI non-responders
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0558 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - Survival curves are not statistically different

    Secondary: Overall survival between treatment and placebo arms

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    End point title
    		 Overall survival between treatment and placebo arms [5]
    End point description
    End point type
    Secondary
    End point timeframe
    05/09/2012 - 15/09/2018
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Screen fails (arm) were not assessed for any end point
    End point values
    		 Axitinib Placebo
    Number of subjects analysed
    34
    17
    Units: Days
        median (full range (min-max))
    175.0 (20 to 893)
    169.0 (36 to 875)
    Attachments
    		 Overall Survival: Drug vs Placebo
    Statistical analysis title
    		 Comparison of OS of Drug Vs Placebo
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3173 [6]
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - Survival curves are not statistically different

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 30 days following end of treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1.1
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2016
    At this time, Pfizer is making a switch from providing commercial image debossed tablets and matching debossed placebo to non-debossed tablets and matching non-debossed placebo with the intent to secure the commercial supply chain. It is therefore necessary to change from the cross-reference currently in place that references Study A4061032: Axitinib (Ag-013736) as Second Line Therapy For Metastatic Renal Cell Cancer: Axis Trial, EudraCT 2008-001451-21 to a new Investigational Medicinal Product Dossier - Quality (IMPD-Q).

    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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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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