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    Clinical Trial Results:
    Phase I Trial of CEDIRANIB (AZD2171), an Orally Bioavailable Antiangiogenic Agent, in Children and Adolescents With Refractory or Recurrent Solid Tumors

    Summary
    EudraCT number
    2012-001155-39
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    01 Oct 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Mar 2016
    First version publication date
    31 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    060152, 06-C-0152, D8480C00016
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00321581
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    NA, Sodertalje, Sweden, S-151-85
    Public contact
    Information Centre, AstraZeneca, Information.centre@astrazeneca.com
    Scientific contact
    Information Centre, AstraZeneca, Information.centre@astrazeneca.com
    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
    08 Aug 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of orally administered cediranib on a daily dose for 28 consecutive days schedule in children and adolescents with refractory childhood solid tumors. • Define the toxicity spectrum of oral cediranib in children and adolescents. • Assess the pharmacokinetics of oral cediranib in the pediatric population.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/Good Clinical Practice (GCP). Patients who were 18 years of age were offered the opportunity to assign a Durable Power of Attorney (DPA) so that another person could make decisions about their medical care if they became incapacitated or cognitively impaired. Adults (18 years and over) who were cognitively impaired prior to study entry and who have not previously assigned DPA to a family member or friend were not eligible for the study, because they could not give informed consent. All patients or their legal guardians (if the patients were <18 years old) signed an informed consent form prior to the determination of patient eligibility. After confirmation of patient eligibility all patients or their legal guardians voluntarily signed the IRB approved informed consent form to document their understanding of the investigational nature and the risks of the study before any protocol related procedures were performed. The parent who signed the consent for a minor was a legally recognized parent or guardian. Where deemed appropriate by the clinician and the child's parents or guardian, the child was also included in all discussions about the study and verbal assent obtained. Investigators from the Pharmacology & Experimental Therapeutics Section of the Paediatric Oncology Branch, or investigators from participating institutions, led these discussions. The study was conducted by paediatric oncologists who have extensive experience in performing investigational drug studies in children
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    18
    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)
    4
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    18
    Number of subjects completed
    18

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dose level 8 mg/m2/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg/m2/d

    Arm title
    Dose level 12 mg/m2/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 mg/m2/d

    Arm title
    Dose level 17 mg/m2/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    17 mg/m2/d

    Number of subjects in period 1
    Dose level 8 mg/m2/d Dose level 12 mg/m2/d Dose level 17 mg/m2/d
    Started
    3
    10
    5
    Completed
    3
    10
    5
    Period 2
    Period 2 title
    Dose escalation
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1 - Dose level 12 mg/m2/d
    Arm description
    Dose level 12 mg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 mg/m2/d

    Arm title
    Cohort 2 - Dose level 8 mg/m2/d
    Arm description
    Dose level 8 mg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg/m2/d

    Arm title
    Cohort 3 - Dose level 12 mg/m2/d
    Arm description
    Dose level 12 mg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 mg/m2/d

    Arm title
    Cohort 4 - Dose level 17 mg/m2/d
    Arm description
    Dose level 17 mg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    17 mg/m2/d

    Number of subjects in period 2
    Cohort 1 - Dose level 12 mg/m2/d Cohort 2 - Dose level 8 mg/m2/d Cohort 3 - Dose level 12 mg/m2/d Cohort 4 - Dose level 17 mg/m2/d
    Started
    2
    3
    8
    5
    Completed
    2
    3
    8
    5
    Period 3
    Period 3 title
    Overall Study
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dose level 8 mg/m2/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg/m2/d

    Arm title
    Dose level 12 mg/m2/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 mg/m2/d

    Arm title
    Dose level 17 mg/m2/d
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    17 mg/m2/d

    Number of subjects in period 3
    Dose level 8 mg/m2/d Dose level 12 mg/m2/d Dose level 17 mg/m2/d
    Started
    3
    10
    5
    Completed
    0
    0
    0
    Not completed
    3
    10
    5
         30 days after last dose
    -
    1
    1
         30 days off therapy
    -
    1
    -
         Redused treatment
    -
    1
    1
         Adverse event, serious fatal
    -
    2
    -
         Consent withdrawn by subject
    -
    3
    1
         Disease progression
    3
    1
    -
         Lost to follow-up
    -
    1
    2

    Baseline characteristics

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

    Reporting group values
    Overall Study Total
    Number of subjects
    18 18
    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)
    4 4
        Adolescents (12-17 years)
    12 12
        Adults (18-64 years)
    2 2
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    15 (8 to 18) -
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    10 10
    Diagnosis
    Units: Subjects
        Ewing sarcoma
    4 4
        Osteosarcoma
    4 4
        Synovial sarcoma recurrent
    2 2
        Alveolar soft part sarcoma recurrent
    2 2
        Other
    6 6

    End points

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    End points reporting groups
    Reporting group title
    Dose level 8 mg/m2/d
    Reporting group description
    -

    Reporting group title
    Dose level 12 mg/m2/d
    Reporting group description
    -

    Reporting group title
    Dose level 17 mg/m2/d
    Reporting group description
    -
    Reporting group title
    Cohort 1 - Dose level 12 mg/m2/d
    Reporting group description
    Dose level 12 mg/m2/d

    Reporting group title
    Cohort 2 - Dose level 8 mg/m2/d
    Reporting group description
    Dose level 8 mg/m2/d

    Reporting group title
    Cohort 3 - Dose level 12 mg/m2/d
    Reporting group description
    Dose level 12 mg/m2/d

    Reporting group title
    Cohort 4 - Dose level 17 mg/m2/d
    Reporting group description
    Dose level 17 mg/m2/d
    Reporting group title
    Dose level 8 mg/m2/d
    Reporting group description
    -

    Reporting group title
    Dose level 12 mg/m2/d
    Reporting group description
    -

    Reporting group title
    Dose level 17 mg/m2/d
    Reporting group description
    -

    Primary: Toxicity

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    End point title
    Toxicity [1]
    End point description
    First cycle of treatment
    End point type
    Primary
    End point timeframe
    Cycle 1
    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 dose escalation study, there is no formal statistical analysis.&nbsp;A count of toxicities&nbsp;associated with&nbsp;each dose level is presented
    End point values
    Cohort 1 - Dose level 12 mg/m2/d Cohort 2 - Dose level 8 mg/m2/d Cohort 3 - Dose level 12 mg/m2/d Cohort 4 - Dose level 17 mg/m2/d
    Number of subjects analysed
    2 [2]
    3
    7
    4
    Units: Subject
        Leukopenia
    0
    0
    2
    0
        Neutropenia
    0
    0
    1
    0
        Abdominal pain
    0
    1
    3
    4
        Anorexia
    0
    2
    1
    3
        Constipation
    0
    0
    1
    2
        Diarrhea
    1
    1
    2
    4
        Stomatitis
    0
    0
    0
    1
        Nausea
    1
    1
    4
    4
        Vomiting
    1
    0
    1
    2
        Fatigue
    0
    1
    4
    1
        lethargy
    1
    0
    0
    0
        Weight loss
    0
    1
    2
    2
        Prolonger QTc
    1
    0
    0
    0
        Premature ventricular complexes
    1
    0
    0
    0
        Decreased left ventricular function
    1
    2
    1
    1
        Hypertension
    1
    0
    0
    1
        Infection, Grade 1 or 2 ANC
    0
    0
    2
    0
        Increased AST
    1
    0
    0
    1
        Increased ALT
    1
    0
    0
    1
        Hypoalbuminemia
    0
    0
    2
    0
        Hypoglycemia
    0
    1
    0
    0
        Proteinuria
    0
    1
    0
    0
        Chest pain
    0
    0
    0
    2
        Headache
    0
    0
    2
    2
        Cystitis
    0
    1
    0
    0
    Notes
    [2] - Both patients had DLT.Dose de-escalated to 8 mg/m2/d,re-escalated to12mg/m2/d,then 17mg/m2/d
    No statistical analyses for this end point

    Secondary: AUC

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    End point title
    AUC
    End point description
    End point type
    Secondary
    End point timeframe
    48 hours
    End point values
    Dose level 8 mg/m2/d Dose level 12 mg/m2/d Dose level 17 mg/m2/d
    Number of subjects analysed
    3
    7
    2
    Units: ngxh/mL
    arithmetic mean (geometric coefficient of variation)
        0-24hrs
    440 ± 36
    800 ± 45
    1140 ± 96
        0-48hrs
    530 ± 37
    1000 ± 44
    1570 ± 95
        0-inf
    540 ± 39
    1070 ± 43
    1870 ± 95
    No statistical analyses for this end point

    Secondary: Cmax

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    End point title
    Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    48 hours
    End point values
    Dose level 8 mg/m2/d Dose level 12 mg/m2/d Dose level 17 mg/m2/d
    Number of subjects analysed
    3
    7
    2
    Units: ng/mL
        arithmetic mean (geometric coefficient of variation)
    52 ± 46
    70 ± 35
    106 ± 105
    No statistical analyses for this end point

    Secondary: Tmax

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    End point title
    Tmax
    End point description
    Tmax
    End point type
    Secondary
    End point timeframe
    48 hours
    End point values
    Dose level 8 mg/m2/d Dose level 12 mg/m2/d Dose level 17 mg/m2/d
    Number of subjects analysed
    3
    7
    2
    Units: hours
        median (full range (min-max))
    3 (2.1 to 4)
    4 (2.2 to 8.2)
    4.5 (3 to 6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to end of study
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    12 mg/m2
    Reporting group description
    Dose level 12 mg/m2

    Reporting group title
    8 mg/m2
    Reporting group description
    Dose level 8mg/m2

    Reporting group title
    17 mg/m2
    Reporting group description
    Dose level 17mg/m2

    Serious adverse events
    12 mg/m2 8 mg/m2 17 mg/m2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    1 / 3 (33.33%)
    2 / 5 (40.00%)
         number of deaths (all causes)
    7
    0
    2
         number of deaths resulting from adverse events
    2
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    12 mg/m2 8 mg/m2 17 mg/m2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Hypertension
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 3 (33.33%)
    2 / 5 (40.00%)
         occurrences all number
    6
    1
    4
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    3 / 5 (60.00%)
         occurrences all number
    3
    0
    6
    Fatigue
         subjects affected / exposed
    7 / 10 (70.00%)
    2 / 3 (66.67%)
    3 / 5 (60.00%)
         occurrences all number
    10
    7
    10
    Ill-defined disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    3 / 5 (60.00%)
         occurrences all number
    16
    2
    5
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    2 / 5 (40.00%)
         occurrences all number
    3
    3
    11
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    2
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    11
    Blood albumin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    5
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    2
    Blood calcium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Blood calcium increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Blood glucose decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    4
    0
    1
    Ear, nose and throat examination abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Haemoglobin urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    4
    4
    0
    Protein urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 3 (66.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    3
    2
    0
    Weight decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 3 (66.67%)
    4 / 5 (80.00%)
         occurrences all number
    8
    2
    7
    White blood cell count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    5
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Atrial tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    Cardiac disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Left ventricular failure
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 3 (100.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    3
    1
    Palpitations
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Pericarditis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    3
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchospasm
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
    2 / 5 (40.00%)
         occurrences all number
    3
    4
    2
    Dysphonia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 3 (66.67%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    2
    Epistaxis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumothorax
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    7
    0
    3
    Blood and lymphatic system disorders
    Lymphatic disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Headache
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 3 (33.33%)
    3 / 5 (60.00%)
         occurrences all number
    14
    1
    27
    Eye disorders
    Eyelid function disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 3 (33.33%)
    4 / 5 (80.00%)
         occurrences all number
    10
    3
    13
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    3 / 5 (60.00%)
         occurrences all number
    5
    1
    4
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    7 / 10 (70.00%)
    2 / 3 (66.67%)
    5 / 5 (100.00%)
         occurrences all number
    57
    5
    21
    Nausea
         subjects affected / exposed
    8 / 10 (80.00%)
    1 / 3 (33.33%)
    4 / 5 (80.00%)
         occurrences all number
    10
    8
    21
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    3
    Tooth disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 3 (33.33%)
    3 / 5 (60.00%)
         occurrences all number
    7
    1
    8
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Urogenital disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Exfoliative rash
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    0
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Pruritus
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    5
    2
    0
    Skin disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 3 (66.67%)
    0 / 5 (0.00%)
         occurrences all number
    1
    5
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 5 (40.00%)
         occurrences all number
    2
    1
    3
    Bone pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    3 / 5 (60.00%)
         occurrences all number
    1
    0
    5
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
         occurrences all number
    1
    6
    4
    Neck pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 3 (33.33%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 3 (66.67%)
    4 / 5 (80.00%)
         occurrences all number
    6
    3
    7
    Dehydration
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 3 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    13
    0
    2
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 3 (66.67%)
    0 / 5 (0.00%)
         occurrences all number
    5
    5
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2007
    The first protocol amendment (CSP Version 01 Aug 07) was initiated to update hypertension management guidelines, clarify the dose limiting hypertension and proteinuria and add DCEMRI instructions to the protocol along with other administrative changes.
    28 Jan 2008
    The second protocol amendment (CSP Version 29 Jan 08) was initiated to incorporate an additional dose level (Dose level -1 (8 mg/m2)) and to increase the study accrual to n=40. EKG and electrocardiogram safety monitoring assessments were incorporated along with update thyroid dysfunction management guidelines. Eligibility criteria were updated to incorporate to add cardiac dysfunction and the safety measures for the assessment of prolonged QTc. Updated information on dose limiting toxicities was added to the protocol along with other administrative changes.
    11 Feb 2009
    The third protocol amendment (CSP Version 11 Feb 09) was initiated to incorporate non-contrast MRI measures to assess distal femoral growth plate in patients. Information on how to disperse cediranib tablets for oral dosing was added to the protocol along with updated safety data from the data from Investigator Brochure. Consent form revisions were also made along with other administrative changes.
    09 Mar 2009
    The fourth protocol amendment (CSP Version 03 Mar 09) was initiated to remove the exclusion of patients with brain metastases. Updates data on the activity of cediranib in alveolar soft part sarcoma was added to the protocol along with other administrative changes.
    01 Oct 2009
    The fifth protocol Amendment (CSP Version 01 Oct 09) was initiated to clarify inconsistencies in the protocol regarding criteria for dose escalation and dose interruptions. The number of children <12 to be treated at the MTD was increased from 3 to 6, therefore increasing the accrual ceiling from 33 to 36. The risk of pneumothorax was added to the protocol and consent form along with other administrative changes.
    30 Nov 2009
    The sixth protocol amendment (CSP Version 30 Nov 09) was initiated to record a change in Principle Investigator. The amendment also covered the removal of AML cohort at the request of the sponsor and clarification of timing of grow plate analysis (Scanograms and MRI). The interval between tumor restaging evaluations after cycle 8 was increased from every 2 months to every 4 months along with other administrative changes.

    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.
    Study sponsored by AZ, conducted by NCI; analysis and reporting was performed exclusively by NCI group [see link]. To provide as complete a report online as possible, summaries for demo, AE were generated by AZ for all 18 patients who received drug.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/21060028
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