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    Clinical Trial Results:
    A Phase II Study of Axitinib in Patients with Metastatic Renal Cell Cancer Unsuitable for Nephrectomy

    Summary
    EudraCT number
    2011-004562-16
    Trial protocol
    GB  
    Global end of trial date
    28 Feb 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2023
    First version publication date
    15 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ICR-CTSU/2011/10033
    Additional study identifiers
    ISRCTN number
    ISRCTN72679844
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Sponsor Identification Number: CCR3587, ICR-CTSU Protocol Number: ICR-CTSU/2011/10033, REC reference: 12/LO/0639, IRAS: 98117
    Sponsors
    Sponsor organisation name
    The Institute of Cancer Research
    Sponsor organisation address
    15 Cotswold Road, London, United Kingdom, SM2 5NG
    Public contact
    Rebecca Lewis, The Institute of Cancer Research, 44 02087224081, apredict-icrctsu@icr.ac.uk
    Scientific contact
    Rebecca Lewis, The Institute of Cancer Research, 44 02087224081, apredict-icrctsu@icr.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
    03 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does treatment with axitinib stop previously untreated widespread kidney cancer that can't be surgically removed from getting worse for at least 6 months?
    Protection of trial subjects
    For trial entry and optional tissue donation, patients were given a verbal explanation, discussion and written information. The Principal Investigator at each site was responsible for ensuring written informed consent was obtained for each patient. Eligible patients were given as much time as they needed to consider and come to a decision about entering the trial, prior to giving consent for registration. The patient information sheet, described fully which parties would have access to their identifiable personal information and patients were asked to give consent to this. The trial was overseen by an Independent Data Monitoring Committee, who reviewed the accumulating trial data and could recommend stopping the trial if there was any cause for concern about patient safety and if this were the case the patient's oncologist would be notified.
    Background therapy
    Renal cell carcinoma (RCC) is diagnosed in around 8,500 patients and accounts for approximately 3% of malignant disease annually in the UK. Many patients initially present with advanced or unresectable disease and up to 30% of patients treated by nephrectomy with curative intent for localised disease will relapse. The 5-year survival rate for metastatic RCC (mRCC) is less than 10%. Historically the prognosis for metastatic RCC was poor with a median survival of 6-8 months and reported response rates to chemotherapy and hormonal agents have been of the order of only 5-10%. Approximately half of RCC tumours have mutations in the Von Hippel-Lindau gene (VHL). VHL loss increases expression of the hypoxia-inducible factor alpha transcription factors (HIF-1α and HIF-2α). These factors regulate the expression of vascular endothelial growth factor (VEGF) and other molecules implicated in angiogenesis and invasion. These pathways are important in the pathophysiology of RCC although their roles are not fully understood.
    Evidence for comparator
    Nephrectomy is the mainstay of curative treatment for renal cell carcinoma and has also been shown to be of palliative benefit in metastatic disease. Two phase III trials, European Organization Research and Treatment of Cancer 30947 and SouthWest Oncology Group 8949, have demonstrated a survival benefit for nephrectomy followed by interferon versus interferon alone in patients with histologically confirmed progressive renal cell carcinoma and good performance status at presentation. Nephrectomy is generally a relatively safe and well-tolerated operation in experienced hands: a report from Memorial Sloan Kettering Cancer Centre (MSKCC) of 692 radical nephrectomies for renal cell cancer performed between 1995 and 2002 quotes a 3% procedure-related complication rate and 0.2% procedure-related mortality. Axitinib is a potent oral VEGFR2 and 3 inhibitor at picomolar concentrations and VEGFR1, PDGFRs and c-KIT inhibitor at low nanomolar concentrations. In phase II clinical trials, axitinib has shown efficacy in sorafenib and cytokine refractory mRCC patients. A recently reported phase III trial, showed superiority over sorafenib as second line therapy, leading to the licensing of axitinib in this indication by the US Food and Drug Administration (FDA) agency in January 2012. Axitinib was subsequently licensed for the same indication by the European Medicines Agency. Furthermore, the efficacy of axitinib is under evaluation in other tumour types, and has shown activity in lung, thyroid, and pancreatic cancers, and melanoma.
    Actual start date of recruitment
    01 Jun 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: 65
    Worldwide total number of subjects
    65
    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)
    36
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between 10 October 2012 and 23 December 2016, 65 participants were registered into A-PREDICT from 11 UK hospitals.

    Pre-assignment
    Screening details
    Patients who met the eligibility criteria were recruited. Eligible patients had histologically confirmed metastatic renal cell carcinoma of predominant clear cell histology and who were not immediately clinically indicated for debulking nephrectomy (as judged by the treating clinician). Patients were over 18 with no prior systemic therapy.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    Axitinib
    Arm description
    All participants started open-label axitinib on 5mg dose taken orally, twice daily, until clinical benefit was no longer derived
    Arm type
    Experimental

    Investigational medicinal product name
    Axitinib
    Investigational medicinal product code
    Other name
    Inlyta
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were prescribed a starting dose of 5mg tablet BID. Patients who tolerated axitinib with no adverse events related to study drug above CTCAE grade 2 for a consecutive 2-week period could have their dose increased by one dose level to a maximum of 10 mg BID (unless the patient’s blood pressure [BP] was >150/90 mm Hg or the patient was receiving antihypertensive medication). If the patient received antihypertensive medication and a dose escalation was clinically indicated TMG approval was obtained for the proposed dose escalation. No patient receiving antihypertensive medication could have an axitinib dose escalation without prior TMG approval.

    Number of subjects in period 1
    Axitinib
    Started
    65
    Completed
    65

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial (overall period)
    Reporting group description
    -

    Reporting group values
    Overall Trial (overall period) Total
    Number of subjects
    65 65
    Age categorical
    Age at registration in years
    Units: Subjects
        40-49 years
    8 8
        50-59 years
    19 19
        60-69 years
    26 26
        70+ years
    12 12
    Age continuous
    Age at registration in years
    Units: years
        median (inter-quartile range (Q1-Q3))
    63.5 (56.7 to 69.0) -
    Gender categorical
    Units: Subjects
        Female
    22 22
        Male
    43 43
    Histological type
    Units: Subjects
        Clear cell
    62 62
        Clear cell and chromophobe
    2 2
        Clear cell and sarcomatoid component
    1 1
    Fuhrman grade
    Units: Subjects
        G1
    2 2
        G2
    26 26
        G3
    21 21
        G4
    2 2
        Unobtainable
    14 14
    Motzer Score
    Units: Subjects
        Intermediate risk
    50 50
        High risk
    15 15
    Subject analysis sets

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This population contains all people registered into the study (regardless of whether they were later found to be ineligible, a protocol deviator, never treated etc.).

    Subject analysis sets values
    Intention to treat
    Number of subjects
    65
    Age categorical
    Age at registration in years
    Units: Subjects
        40-49 years
        50-59 years
        60-69 years
        70+ years
    Age continuous
    Age at registration in years
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
        Male
    Histological type
    Units: Subjects
        Clear cell
    62
        Clear cell and chromophobe
    2
        Clear cell and sarcomatoid component
    1
    Fuhrman grade
    Units: Subjects
        G1
    2
        G2
    26
        G3
    21
        G4
    2
        Unobtainable
    14
    Motzer Score
    Units: Subjects
        Intermediate risk
    50
        High risk
    15

    End points

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    End points reporting groups
    Reporting group title
    Axitinib
    Reporting group description
    All participants started open-label axitinib on 5mg dose taken orally, twice daily, until clinical benefit was no longer derived

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This population contains all people registered into the study (regardless of whether they were later found to be ineligible, a protocol deviator, never treated etc.).

    Primary: Proportion of patients free from disease progression

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    End point title
    Proportion of patients free from disease progression [1]
    End point description
    The proportion of patients treated with axitinib who are free from disease progression 6 months from the commencement of treatment according to RECIST v1.1 criteria.
    End point type
    Primary
    End point timeframe
    6 months from the commencement of treatment
    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: This is a single arm study and no comparative analysis was performed, however the system expects at least 2 groups to be identified. All methods and options specified in the analysis section apply to statistical methods and summary measures to report and compare at least 2 independent groups, which is not the case in this single arm trial. There is no way of reporting one group inference and summary values without triggering an error or reporting inaccurate information.
    End point values
    Axitinib Intention to treat
    Number of subjects analysed
    65
    65
    Units: Percentage
        number (confidence interval 58.5%)
    58.5 (45.6 to 70.6)
    58.5 (45.6 to 70.6)
    No statistical analyses for this end point

    Secondary: Best overall response

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    End point title
    Best overall response
    End point description
    Best overall response is defined as the best tumour response that is achieved during or within 30 days after termination of axitinib that is confirmed according to RECIST.
    End point type
    Secondary
    End point timeframe
    Best response as calculated while patients are on treatment.
    End point values
    Axitinib Intention to treat
    Number of subjects analysed
    65
    65
    Units: Number
        CR
    1
    1
        PR
    19
    19
        SD
    29
    29
        PD
    16
    16
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    Progression free survival
    End point description
    Progression-free survival (PFS) is measured from the date of registration until first date of either death or confirmed progressive disease according to RECIST 1.1. Time to last follow-up is used if patient has not progressed or died and PFS time for the patient is considered censored.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Axitinib Intention to treat
    Number of subjects analysed
    65
    65
    Units: Survival time
        number (confidence interval 63.1%)
    63.1 (50.2 to 74.7)
    63.1 (50.2 to 74.7)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    OS is defined as time from registration to death from any cause. Patients who have not been reported to have died are censored at last follow-up.
    End point type
    Secondary
    End point timeframe
    Median survival time based on all follow-up available.
    End point values
    Axitinib Intention to treat
    Number of subjects analysed
    65
    65
    Units: Months
        median (inter-quartile range (Q1-Q3))
    19.7 (9.2 to 37.2)
    19.7 (9.2 to 37.2)
    No statistical analyses for this end point

    Secondary: Proportion of patients who undergo nephrectomy

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    End point title
    Proportion of patients who undergo nephrectomy
    End point description
    The proportion of patients who undergo nephrectomy following registration as a result of treatment with axitinib will be reported.
    End point type
    Secondary
    End point timeframe
    Whilst patients are on treatment.
    End point values
    Axitinib Intention to treat
    Number of subjects analysed
    65
    65
    Units: Percentage
        number (confidence interval 13.8%)
    9 (6.5 to 24.7)
    9 (6.5 to 24.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 28 days of the patient receiving study drug.
    Adverse event reporting additional description
    Progression of the malignancy was not reported as a serious adverse event. Hospitalisation due to signs and symptoms of malignancy progression was not reported as a serious adverse event. Occurrences are counted as any subject reporting a particular AE at a visit where toxicity was assessed.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Axitinib
    Reporting group description
    This population contains all patients who received at least one dose of axitinib.

    Serious adverse events
    Axitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 64 (40.63%)
         number of deaths (all causes)
    62
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Productive cough
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood calcium increased
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Wound dehiscence
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Urinary retention
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Hyponatraemia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Axitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 64 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    19
    Hypertension
         subjects affected / exposed
    60 / 64 (93.75%)
         occurrences all number
    881
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    11 / 64 (17.19%)
         occurrences all number
    15
    Fatigue
         subjects affected / exposed
    61 / 64 (95.31%)
         occurrences all number
    651
    Mucosal inflammation
         subjects affected / exposed
    32 / 64 (50.00%)
         occurrences all number
    157
    Oedema peripheral
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    9
    Pain
         subjects affected / exposed
    11 / 64 (17.19%)
         occurrences all number
    50
    Pyrexia
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    13
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 64 (39.06%)
         occurrences all number
    105
    Dysphonia
         subjects affected / exposed
    26 / 64 (40.63%)
         occurrences all number
    190
    Dyspnoea
         subjects affected / exposed
    29 / 64 (45.31%)
         occurrences all number
    145
    Epistaxis
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 64 (26.56%)
         occurrences all number
    99
    Mood altered
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    22
    Blood creatinine decreased
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    11
    Blood creatinine increased
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    23
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    25
    Blood magnesium decreased
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    13
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    26
    Lymphocyte count decreased
         subjects affected / exposed
    11 / 64 (17.19%)
         occurrences all number
    49
    Platelet count increased
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    8
    Prothrombin time prolonged
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    9
    Weight decreased
         subjects affected / exposed
    28 / 64 (43.75%)
         occurrences all number
    166
    Injury, poisoning and procedural complications
    Wound complication
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 64 (18.75%)
         occurrences all number
    44
    Dysgeusia
         subjects affected / exposed
    28 / 64 (43.75%)
         occurrences all number
    167
    Headache
         subjects affected / exposed
    16 / 64 (25.00%)
         occurrences all number
    35
    Neuralgia
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    7
    Neuropathy peripheral
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    8
    Paraesthesia
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 64 (20.31%)
         occurrences all number
    24
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    26 / 64 (40.63%)
         occurrences all number
    131
    Constipation
         subjects affected / exposed
    27 / 64 (42.19%)
         occurrences all number
    189
    Diarrhoea
         subjects affected / exposed
    38 / 64 (59.38%)
         occurrences all number
    434
    Dry mouth
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    15 / 64 (23.44%)
         occurrences all number
    56
    Mouth ulceration
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    14
    Nausea
         subjects affected / exposed
    38 / 64 (59.38%)
         occurrences all number
    181
    Oral pain
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    25
    Stomatitis
         subjects affected / exposed
    22 / 64 (34.38%)
         occurrences all number
    90
    Vomiting
         subjects affected / exposed
    24 / 64 (37.50%)
         occurrences all number
    79
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    12
    Dry skin
         subjects affected / exposed
    20 / 64 (31.25%)
         occurrences all number
    54
    Night sweats
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    31
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    23 / 64 (35.94%)
         occurrences all number
    217
    Pruritus
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    10
    Rash
         subjects affected / exposed
    20 / 64 (31.25%)
         occurrences all number
    85
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    38 / 64 (59.38%)
         occurrences all number
    234
    Renal pain
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    11
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Hypothyroidism
         subjects affected / exposed
    28 / 64 (43.75%)
         occurrences all number
    194
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 64 (35.94%)
         occurrences all number
    204
    Back pain
         subjects affected / exposed
    37 / 64 (57.81%)
         occurrences all number
    236
    Bone pain
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    16
    Flank pain
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    7
    Joint swelling
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    17
    Muscle spasms
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Muscular weakness
         subjects affected / exposed
    20 / 64 (31.25%)
         occurrences all number
    56
    Musculoskeletal chest pain
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    16
    Musculoskeletal pain
         subjects affected / exposed
    13 / 64 (20.31%)
         occurrences all number
    71
    Musculoskeletal stiffness
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    8
    Myalgia
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    33
    Pain in extremity
         subjects affected / exposed
    21 / 64 (32.81%)
         occurrences all number
    101
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    13
    Nasopharyngitis
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 64 (70.31%)
         occurrences all number
    243
    Hypercalcaemia
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    7
    Hyperglycaemia
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    41
    Hypoalbuminaemia
         subjects affected / exposed
    13 / 64 (20.31%)
         occurrences all number
    34
    Hyponatraemia
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    17

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2012
    Protocol amendment to trial assessments and drug dispensing schedule. An additional pregnancy test was included to be conducted within 3 days prior to commencing treatment. The timeframe for stopping axitinib prior to day 1 week 9 biopsy was extended from 7 days to 5-7 days. Timelines for response assessment and biopsy when the patient stopped trial treatment were inserted. The schedule of assessments was amended in line with these changes. A “Subsequent Therapy” section was added confirm that “Participants for whom treatment is discontinued should be treated according to clinical circumstances and should be managed at the local clinician’s discretion.” Addition of new participating centres.
    25 Jan 2013
    Amendment to the Patient Information Sheet and Consent Form relating to the frequency of hospital visits and details regarding participant biopsies. Addition of new participating centres.
    25 Oct 2013
    The study Reference Safety Information (RSI) had been updated to the Summary of Medical Product Characteristics (SmPC), and any reference to the Investigator Brochure (IB) in the protocol had been replaced by SmPC. The protocol was revised throughout for consistency with the SmPC. The protocol was updated to state that eligible patients included those with unresectable primary tumours, those with a large metastatic burden or those unfit for nephrectomy. Further changes were included to the timing of scheduled assessments and guidance around treatment interruptions. Addition of new participating centres and a change in Principal Investigator at a participating centre.
    16 May 2014
    The protocol was amended to clarify that where a patient received antihypertensive medication and a dose escalation was clinically indicated, this was permitted with TMG approval on a case-by-case basis. The urinalysis section of the protocol was amended allow an additional method in the assessment for proteinuria. Centres may use urinary protein:creatinine ratio (PCR).
    13 May 2015
    The protocol was amended to note the London Research Institute (LRI) had become part of the Francis Crick Institute (FCI); the addition of an exploratory endpoint to investigate any effect of treatment on the extent of inferior vena cava (IVC) venous tumour thrombus (VTT); provision to allow the use of prohibited medications in exceptional circumstances if approved by the Chief Investigator, and a minor correction to the translational sample schedule. Change of principal investigator at an existing site.
    26 Nov 2015
    The protocol inclusion criteria were updated to state that adequate organ function can be defined by an AST or ALT reading rather than requiring both and that the baseline systolic BP readings must be ≤150 mm Hg in accordance with the current SmPC. Change in Principal Investigator at an existing centre.
    08 Nov 2016
    The protcol exclusion criteria were update to include known galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Guidance relating to dose modification for axitinib related adverse events; dose reduction for proteinuria; and concomitant therapy were added to the protocol in line with the new version of Reference Safety Information. Changes to dose reduction guidance for hypertension for consistency with systolic pressure guidance Collection of fresh tissue for cell culture from London sites removed as no longer required The Patient Information Sheet's Serious and Common side effects section was revised in light of updated Reference Safety Information.
    24 Jan 2017
    Closure to recruitment. A-PREDICT closed to recruitment on 23/12/2016 following feedback from the Independent Data Monitoring and Steering Committee, who met on the 01/12/2016. The IDMSC reviewed the number of A-PREDICT participants progression free at week 24 and advised recruitment should close as no further participants were required to assess the primary objective, 65 participants were recruited in total. the original sample size was 99 participants. The recommendation to close to recruitment was not based on any safety reasons. Participants receiving treatment at the time of closure continued on treatment as per protocol.
    02 Nov 2018
    Protocol amendment detailing the introduction of a new axitinib supply process following transfer of participants to commercial supply after expiration of the existing trial supply on 31/11/2018.
    12 Jun 2019
    Update to reference safety information. The patient information sheet was updated in line with the new reference safety information and to include statement to explain translational analysis of samples collected in A-PREDICT may occur outside of the Francis Crick Institute either in the UK or abroad.
    02 Jun 2020
    The reference safety information was updated due to the release of the axitinib (Inlyta) SmPC in which cholecystitis had been added as a common adverse event. The protocol follow up schedule had been rationalised for patients who had been on treatment for a considerable amount of time as four weekly assessment was no longer clinically required after this duration on treatment. Hospital visits were aligned with scan frequency for the convenience of participants.

    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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