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    Clinical Trial Results:
    A Phase II Study Of Sunitinib And Low Dose Metronomic Cyclophosphamide In Advanced Renal Cell Cancer

    Summary
    EudraCT number
    2008-008676-13
    Trial protocol
    GB  
    Global end of trial date
    31 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2019
    First version publication date
    28 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3164
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    The Royal Marsden NHS Foundation Trust
    Sponsor organisation address
    Fulham Road, London, United Kingdom, SW36JJ
    Public contact
    Lyra Del Rosario, The Royal Marsden NHS Foundation Trust, +44 2078082710, Lyra.DelRosario@rmh.nhs.uk
    Scientific contact
    Lyra Del Rosario, The Royal Marsden NHS Foundation Trust, +44 2078082710, Lyra.DelRosario@rmh.nhs.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
    31 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and toxicity of the combination of sunitinib and low dose cyclophosphamide To eludicate possible mechanisms of action by measuring serum and angiogenic factors and molecular markers in tumours
    Protection of trial subjects
    Patients are closely monitored during the study by the investigator and other delegated clinical members of the research team. Conducting regular tests and procedures to asses clinical status of the patients are written into the protocol to detect adverse events early on, minimising worsening of symptoms.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    28 Sep 2009
    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: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    10
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Potential patients were identified by the Principal Investigator, Sub-Investigators and research nurses during out-patients clinics. Patients were given trial information and adequate time (>24hrs) to consider study entry. Recruitment duration was 2 years from study opening.

    Pre-assignment
    Screening details
    Screening evaluations were performed to confirm eligibility. Nineteen (19) patients were consented and enrolled into the trial. There were no screen failures and this analysis includes all nineteen patients .

    Period 1
    Period 1 title
    Baseline, Study Treatment and Follow-up (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    Arm 1
    Arm description
    This study is single-arm. All patients received Sunitinib and Cyclophosphamide. Treatment continues for as long as patients are judged to be gaining clinical benefit by their clinician.
    Arm type
    Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    LO1XE04
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    50mg once daily starting on Day 1 for 4 weeks followed by a 2 week break. This will be defined as one cycle of treatment.

    Investigational medicinal product name
    Cyclophosphamide (low dose)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg daily

    Number of subjects in period 1
    Arm 1
    Started
    19
    Completed
    18
    Not completed
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    This study is single-arm. All patients received Sunitinib and Cyclophosphamide. Treatment continues for as long as patients are judged to be gaining clinical benefit by their clinician.

    Reporting group values
    Arm 1 Total
    Number of subjects
    19 19
    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)
    10 10
        From 65-84 years
    9 9
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    11 11
    Histology
    Units: Subjects
        Clear Cell
    18 18
        Papillary
    1 1
    Stage at initial diagnosis
    Units: Subjects
        Stage I
    1 1
        Stage II
    1 1
        Stage III
    8 8
        Stage IV
    9 9
    AJCC grading at initial diagnosis
    Units: Subjects
        G2 (Intermediate grade)
    2 2
        G3 (Poorly Differentiated, high grade)
    10 10
        G4 (Undifferentiated, high grade)
    3 3
        GX (Undifferentiated)
    3 3
        Not Known
    1 1
    Status of disease at study entry
    Units: Subjects
        Stage III
    1 1
        Stage IV
    18 18
    MOTZER category
    Units: Subjects
        High (3 or more risk factors)
    1 1
        Intermediate (1 or 2 risk factors)
    8 8
        Low (0 risk factors)
    10 10
    ECOG Performance status >2
    Units: Subjects
        No
    16 16
        Yes
    3 3
    High Lactate Dehydrogenase (>1.5xULN)
    Units: Subjects
        No
    17 17
        Yes
    2 2
    Low Serum Haemoglobin (<LLN)
    Units: Subjects
        No
    14 14
        Yes
    5 5
    High Corrected serum Calcium
    Units: Subjects
        No
    19 19
        Yes
    0 0
    Absence of prior nephrectomy
    Units: Subjects
        No
    17 17
        Yes
    2 2
    Previous Surgery for RCC
    Units: Subjects
        No
    1 1
        Yes
    18 18
    Number of RCC surgery
    Units: Subjects
        One
    17 17
        Two
    1 1
        None
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    This study is single-arm. All patients received Sunitinib and Cyclophosphamide. Treatment continues for as long as patients are judged to be gaining clinical benefit by their clinician.

    Subject analysis set title
    Baseline and treatment
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Overall patients recruited and started the experimental drug

    Subject analysis set title
    End of study
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Overall subject who received treatment

    Primary: Overall Response Rate

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    End point title
    Overall Response Rate
    End point description
    End point type
    Primary
    End point timeframe
    Response rate: CT scans are performed at baseline, Cycle 2 Day 36-42, then every even cycle day 36-42. Response rate will be defined as the percentage of patients with their best response of CR or PR using RECIST 1.1 criteria.
    End point values
    Arm 1 Baseline and treatment End of study
    Number of subjects analysed
    19
    19
    19
    Units: Number
        Complete Response
    0
    0
    0
        Partial Response
    8
    8
    8
        Stable Disease
    9
    9
    9
        Progressive Disease
    1
    1
    1
        Never started treatment
    1
    1
    1
    Statistical analysis title
    Overall response rate
    Statistical analysis description
    Proportion of patients responded to treatment (complete or partial response)
    Comparison groups
    Arm 1 v Baseline and treatment v End of study
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Proportion
    Point estimate
    44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22
         upper limit
    69
    Notes
    [1] - Parameter estimate - Overall response rate

    Secondary: Progression Free Survival

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    End point title
    Progression Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 until the end of treatment (progression).
    End point values
    Arm 1 Baseline and treatment End of study
    Number of subjects analysed
    19
    19
    19
    Units: Median in months
        median (confidence interval 95%)
    16.0 (6.9 to 27.6)
    16.0 (6.9 to 27.6)
    16.0 (6.9 to 27.6)
    Statistical analysis title
    Progression free survival
    Statistical analysis description
    Progression free survival defined from date of registration to date of progression or death from any cause. Patients who do not progress or die were censored at last follow up. Kaplan Meier methods was used to calculate median PFS with the 95% confidence intervals.
    Comparison groups
    Arm 1 v End of study v Baseline and treatment
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Median progression free survival
    Point estimate
    16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.9
         upper limit
    27.6
    Notes
    [2] - Parameter estimate - progression free survival

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle one, first dose of drug until death
    End point values
    Arm 1 Baseline and treatment End of study
    Number of subjects analysed
    19
    19
    19
    Units: Median in months
        median (confidence interval 95%)
    21.0 (11.1 to 31.8)
    21.0 (11.1 to 31.8)
    21.0 (11.1 to 31.8)
    Statistical analysis title
    Overall Survival
    Statistical analysis description
    Overall survival defined from date of registration to date of death from any cause. Surviving patients were censored at last follow-up. Kaplan Meier methods was used to calculate median PFS with the 95% confidence intervals.
    Comparison groups
    Arm 1 v Baseline and treatment v End of study
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Median overall survival
    Point estimate
    21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.1
         upper limit
    31.8
    Notes
    [3] - Parameter estimate - Overall survival

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were collected from the day of consent until 30 days after the last administration of the Investigational Medicinal Products.
    Adverse event reporting additional description
    Each adverse event were reported with: onset date, time point and pre-defined expected AE categories including a free-text box for those that does not fall under any of the categories. NCI-CTCAE ver 3 was used to record the severity of each event.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI-CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Single Arm
    Reporting group description
    This study is single arm.

    Serious adverse events
    Single Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
         number of deaths (all causes)
    19
         number of deaths resulting from adverse events
    1
    Investigations
    Disease progression
    Additional description: Disease progression and performance status deterioration
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Blurred vision and loss of speech
    Additional description: CNS cerebrovascular ischemia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage, CNS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bowel ischemia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac ischemia
    Additional description: Chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Transient ischemic attack
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Hemolysis
    Additional description: Patient presented with anaemia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia/Granulocytopenia
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Syncope
    Additional description: Fainting
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Allergic reaction/Hypersensitivity
    Additional description: Allergic reaction to Enalopril
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain
    Additional description: Secondary to disease progression
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Chest Infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Single Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    10 / 19 (52.63%)
         occurrences all number
    10
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Nervous system disorders
    Hand and foot syndrome
         subjects affected / exposed
    11 / 19 (57.89%)
         occurrences all number
    11
    Mood disturbance
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    7
    Neurological disorders
         subjects affected / exposed
    10 / 19 (52.63%)
         occurrences all number
    10
    Paresthesia
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 19 (89.47%)
         occurrences all number
    17
    Flushing
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Mucositis
         subjects affected / exposed
    15 / 19 (78.95%)
         occurrences all number
    15
    Nausea
         subjects affected / exposed
    12 / 19 (63.16%)
         occurrences all number
    12
    Pain
         subjects affected / exposed
    15 / 19 (78.95%)
         occurrences all number
    15
    Vomiting
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Hemorrhage
         subjects affected / exposed
    9 / 19 (47.37%)
         occurrences all number
    18
    Neutropenia
         subjects affected / exposed
    15 / 19 (78.95%)
         occurrences all number
    15
    Thrombocytopenia
         subjects affected / exposed
    13 / 19 (68.42%)
         occurrences all number
    13
    Thrombosis/Embolism
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    14 / 19 (73.68%)
         occurrences all number
    14
    Indigestion
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    9 / 19 (47.37%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 19 (63.16%)
         occurrences all number
    12
    Skin rash
         subjects affected / exposed
    8 / 19 (42.11%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    Aching muscles and joints
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    5
    Bone Pain
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    4
    Infections and infestations
    Infection
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2010
    Protocol updated to ver 4 dated 29-July-2009, patient facing documents and GP letter were also updated.
    09 Dec 2010
    Addition of Mount Vernon Hospital as a site.

    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.
    The study did not meet its recruitment targets but due to changes in the treatment landscapes, it is not beneficial to continue. At the point of notification to the Ethics Committee (31-July-2015), the study did not have any ongoing patients.
    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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