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    Clinical Trial Results:
    Phase II neoadjuvant study of Axitinib for reducing extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion.

    Summary
    EudraCT number
    		 2017-000619-17
    Trial protocol
    		 GB  
    Global end of trial date
    10 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2021
    First version publication date
    23 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NAXIVA v2.0
    Additional study identifiers
    ISRCTN number
    		 ISRCTN96273644
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Common Services Agency
    Sponsor organisation address
    CSA at Public Health Scotland, Edinburgh, United Kingdom, EH12 9EB
    Public contact
    Kathleen Riddle, Scottish Clinical Trials Research Unit, Public Health Scotland, 0131 2757074, Kathleen.Riddle@phs.scot
    Scientific contact
    Prof Grant Stewart, University of Cambridge, 01223 256211, gds35@cam.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
    25 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary research objective is to examine how effective axitinib is at reducing the extent of the cancer invasion into the large blood vessels draining the kidney with a view to reducing the extent of surgery required to then remove the cancerous tissue.
    Protection of trial subjects
    No specific additional measures were implemented for this trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2017
    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: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    7
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were no recurring themes identified from screening logs.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Single arm
    Arm description
    		 Patients taking axitinib.
    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
    The starting dose of axitinib will be 5mg BID and escalated to 7mg BID and then 10mg BID. A dose modification assessment will take place every 2 weeks in clinic during the 8 week pre-surgical treatment period and will be dependent on tolerability of treatment. Patients will follow an aggressive axitinib dose escalation process within the 8 week period to a maximum of 10mg BID. Patients should stop axitinib a minimum of 36 hours and a maximum of 7 days prior to surgery in week 9.

    Number of subjects in period 1
    		Single arm
    Started
    24
    Completed
    18
    Not completed
    6
         Adverse event, serious fatal
    1
         Physician decision
    2
         Did not start trial treatment
    1
         Protocol deviation
    2

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 24 24
    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)
    		 7 7
        From 65-84 years
    		 17 17
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 69 ( 7.94 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all patients in the ITT population who have received at least one dose of the study drug (including any patients who were enrolled in error, received study drug and were subsequently found to be ineligible). In this study, this population is equivalent to the evaluable population.

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population includes all patients registered onto the study.

    Subject analysis set title
    Evaluable population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The evaluable population includes all patients in the ITT population who have received at least one dose of the study drug (including any patients who were enrolled in error, received study drug and were subsequently found to be ineligible).

    Subject analysis set title
    Surgical population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The group of evaluable patients who had surgery.

    Subject analysis sets values
    		 Safety population Intention to treat Evaluable population Surgical population
    Number of subjects
    21
    24
    21
    17
    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)
    6
    7
    6
    6
        From 65-84 years
    15
    17
    15
    11
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        median (standard deviation)
    69 ( 8.16 )
    69 ( 7.94 )
    69 ( 8.16 )
    66 ( 7.83 )
    Gender categorical
    Units: Subjects
        Female
    6
    7
    6
        Male
    15
    17
    15

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 Patients taking axitinib.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all patients in the ITT population who have received at least one dose of the study drug (including any patients who were enrolled in error, received study drug and were subsequently found to be ineligible). In this study, this population is equivalent to the evaluable population.

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population includes all patients registered onto the study.

    Subject analysis set title
    Evaluable population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The evaluable population includes all patients in the ITT population who have received at least one dose of the study drug (including any patients who were enrolled in error, received study drug and were subsequently found to be ineligible).

    Subject analysis set title
    Surgical population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The group of evaluable patients who had surgery.

    Primary: Percentage of evaluable patients with an improvement in disease as a result of taking the study drug

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    End point title
    		 Percentage of evaluable patients with an improvement in disease as a result of taking the study drug
    End point description
    The primary end-point for this study is the percentage of evaluable patients with an improvement in disease as a result of taking the study drug. The definition of an improvement will vary according to the patient’s Mayo Level as captured at screening: * For patients presenting at screening with a Mayo Classification of Level 1 or above, an improvement in disease will be represented by a reduction in their Mayo Classification at week 9. * For patients presenting at screening with a Mayo Classification of Level 0, an improvement in disease will be represented by either: (i) a change of tumor thrombus from main renal vein to branches of the renal vein (on the right); or (ii) a change of tumor thrombus from main renal vein to the renal vein lateral to the gonadal vein (on the left).
    End point type
    Primary
    End point timeframe
    9 weeks
    End point values
    		 Single arm Evaluable population
    Number of subjects analysed
    21
    21
    Units: Patients
        Responder
    6
    6
        Non-responder
    15
    15
    Statistical analysis title
    		 Koyama & Chen (implementation of Simon's 2 stage)
    Statistical analysis description
    The study employed a Simon two stage minimax design to distinguish a <5% from a >25% improvement in the Mayo classification (90% power, 10% 1-sided) requiring 20 patients; interim assessment to be made at 13 patients. Inferences calculatied using: Koyama & Chen, “Proper inference from Simon's two-stage designs.” Statistics in medicine vol. 27,16 (2008): 3145-54.
    Comparison groups
    Single arm v Evaluable population
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.01 [1]
    Method
    		 Koyama & Chen
    Parameter type
    		 Response rate
    Point estimate
    26.58
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 15.76
         upper limit
    		 39.74
    Notes
    [1] - The estimated response rate in this setting is 26.58%, with 80% confidence intervals of (15.76%,39.74%). The exact p-value is 4.413 x10^-4.

    Secondary: Percentage change in surgical approach

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    End point title
    		 Percentage change in surgical approach
    End point description
    End point type
    Secondary
    End point timeframe
    Post-surgical
    End point values
    		 Surgical population
    Number of subjects analysed
    17
    Units: Patients
        Improvement in control of IVC/renal vein
    6
        Deterioration in control of IVC/renal vein
    0
        No change in control of IVC/renal vein
    11
    No statistical analyses for this end point

    Secondary: Percentage change in VTT length

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    End point title
    		 Percentage change in VTT length
    End point description
    End point type
    Secondary
    End point timeframe
    9 weeks
    End point values
    		 Evaluable population
    Number of subjects analysed
    17 [2]
    Units: Percentage
        median (standard deviation)
    21.49 ( 27.60 )
    Notes
    [2] - 3 (no 9wk scan) + 1 (ineligible) pts were not included in the assessment of this timepoint.
    No statistical analyses for this end point

    Secondary: RECIST response

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    End point title
    		 RECIST response
    End point description
    End point type
    Secondary
    End point timeframe
    Week 9
    End point values
    		 Evaluable population
    Number of subjects analysed
    18 [3]
    Units: Patients
        Complete response
    0
        Partial response
    3
        Stable disease
    13
        Progressive disease
    2
        Non-evaluable
    0
    Notes
    [3] - 3 pts did not have the relevant data and were removed from the analysis.
    No statistical analyses for this end point

    Secondary: Evaluation of surgical morbidity assessed by Clavian-Dindo classification

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    End point title
    		 Evaluation of surgical morbidity assessed by Clavian-Dindo classification
    End point description
    End point type
    Secondary
    End point timeframe
    Post-surgery
    End point values
    		 Surgical population
    Number of subjects analysed
    6 [4]
    Units: Patients
        Grade I
    1
        Grade II
    3
        Grade IIIa
    0
        Grade IIIb
    0
        Grade IVa
    0
        Grade IVb
    1
        Grade V
    1
    Notes
    [4] - Only 6 patients had post-surgical complications within 30 days.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Single
    Reporting group description
    		 -

    Serious adverse events
    		 Single
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 24 (33.33%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
    Additional description: Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac disorders
    Additional description: Cardiac disorders
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Nervous system disorders
    Additional description: Nervous system disorders
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Psychiatric disorders
    Additional description: Psychiatric disorders
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
    Additional description: Renal and urinary disorders
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Endocrine disorders
    Additional description: Endocrine disorders
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
    Additional description: Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Single
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    Vascular disorders
    Vascular disorders
    Additional description: Vascular disorders
         subjects affected / exposed
    19 / 24 (79.17%)
         occurrences all number
    89
    General disorders and administration site conditions
    General disorders and administration site conditions
    Additional description: General disorders and administration site conditions
         subjects affected / exposed
    20 / 24 (83.33%)
         occurrences all number
    83
    Reproductive system and breast disorders
    Reproductive system and breast disorders
    Additional description: Reproductive system and breast disorders
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    5
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
    Additional description: Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    16
    Psychiatric disorders
    Psychiatric disorders
    Additional description: Psychiatric disorders
         subjects affected / exposed
    13 / 24 (54.17%)
         occurrences all number
    51
    Investigations
    Investigations
    Additional description: Investigations
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    28
    Cardiac disorders
    Cardiac disorders
    Additional description: Cardiac disorders
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    13
    Nervous system disorders
    Nervous system disorders
    Additional description: Nervous system disorders
         subjects affected / exposed
    13 / 24 (54.17%)
         occurrences all number
    37
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    Additional description: Blood and lymphatic system disorders
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Ear and labyrinth disorders
    Ear and labyrinth disorders
    Additional description: Ear and labyrinth disorders
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Eye disorders
    Eye disorders
    Additional description: Eye disorders
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    7
    Gastrointestinal disorders
    Gastrointestinal disorders
    Additional description: Gastrointestinal disorders
         subjects affected / exposed
    17 / 24 (70.83%)
         occurrences all number
    88
    Hepatobiliary disorders
    Hepatobiliary disorders
    Additional description: Hepatobiliary disorders
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
    Additional description: Skin and subcutaneous tissue disorders
         subjects affected / exposed
    11 / 24 (45.83%)
         occurrences all number
    33
    Renal and urinary disorders
    Renal and urinary disorders
    Additional description: Renal and urinary disorders
         subjects affected / exposed
    11 / 24 (45.83%)
         occurrences all number
    35
    Endocrine disorders
    Endocrine disorders
    Additional description: Endocrine disorders
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
    Additional description: Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    12 / 24 (50.00%)
         occurrences all number
    34
    Infections and infestations
    Infections and infestations
    Additional description: Infections and infestations
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
    Additional description: Metabolism and nutrition disorders
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2017
    Change of PI at Addenbrooke’s (Grant Stewart to Kate Fife): - IRAS SA Form - Cover Letter - Kate Fife (CV & GCP)
    19 Jun 2018
    Addition of a new site: Broomfield Hospital Mid Essex NHS Trust -IRAS SA Form -Cover Letter -Dr Srinivasan (CV & GCP)
    26 Jun 2018
    Protocol amendment (V1.2 to V2.0) - IRAS SA Form - Cover Letter - V2.0 Protocol (clean and tracked) - Main PIS/ICF V2.1 (REC & HRA only)
    20 Sep 2018
    Addition to new site: Royal Free London NHS Foundation Trust - IRAS SA Form - Cover letter - Dr Boleti (CV and GCP)
    05 Dec 2018
    Change of PI at Broomfield - IRAS SA Form - Cover Letter - Abdel Hamid (CV & GCP)
    22 May 2020
    Updated SmPC -Inlyta 5mg SmPC with changes highlighted -Inlyta 7mg SmPC with changes highlighted Please note that the date provided for this amendment is the date we sumitted the amendment. The system will not accept the date that the amendment was approved (17th June 2020) as this is beyond the global end of trial date.

    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.
    Note that this is a single arm trial and the primary endpoint is reported according to the work around reported in point #82 here https://eudract.ema.europa.eu/docs/guidance/EudraCT%20FAQ_for%20publication.pdf.
    For support, Contact us.
    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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