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    Summary
    EudraCT Number:2005-003442-33
    Sponsor's Protocol Code Number:D8480C00038
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-10-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2005-003442-33
    A.3Full title of the trial
    A Phase II, Randomised, Factorial, Double-blind Study to Investigate the Management of AZD2171-induced Hypertension and Efficacy of AZD2171 at Doses of 30 mg and 45 mg in Patients with Advanced Solid Tumours
    A.4.1Sponsor's protocol code numberD8480C00038
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code AZD2171
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAZD2171
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAZD2171
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAZD2171
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Information not present in EudraCT
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Management of AZD2171-induced hypertension in patients with advanced solid tumours
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In order to investigate the hypothesis that withdrawal of AZD2171 can be avoided by controlled anti-hypertensive therapy, the primary objective of the study is to identify a treatment strategy, consisting of a dose of AZD2171 and a hypertension management strategy (pre-defined management of emergent hypertension ± prophylaxis) that is well tolerated without significant drug withdrawal or dose reduction during the first 12 weeks of therapy with AZD2171.
    E.2.2Secondary objectives of the trial
    1. Estimate the activity of AZD2171 monotherapy using objective response rate (ORR) (consisting of CR and PR) and stable disease rate based on RECIST, changes in tumour size and serological markers (where appropriate)
    2. Investigate further the management of AZD2171 induced-hypertension at 30 mg and 45 mg with 2 different hypertension management strategies
    3. Determine safety and tolerability of AZD2171 in combination with anti-hypertensive medication
    4. Determine steady-state pharmacokinetic (PK) parameters of AZD2171
    5. Investigate pharmacodynamic (PD)-PK relationship for AZD2171 and blood pressure (BP)
    Exploratory objectives:
    1. the relationship between AZD2171 and its effects on BP and angiogenesis biomarkers and clinical efficacy
    2. the potential role of known risk factors for hypertension in the development of AZD2171-related hypertension
    3. the potential role of genetic polymorphisms in the development of AZD2171-related hypertension
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Provision of written informed consent.

    2. Males or females aged 18 years and older.

    3. Histological or cytological confirmation of advanced solid tumour, which is refractory to standard therapies or for which no standard therapy exists and for which there is a rationale for the therapeutic use of a VEGFR tyrosine kinase inhibitor.

    4. World Health Organisation (WHO) Performance score 0-2.

    5. Life expectancy of >12 weeks.

    6. One or more measurable lesions at least 10 mm in the longest diameter by spiral computed tomography (CT) scan or 20 mm with conventional techniques (as defined by RECIST).

    7. Patients considered by the investigator to be suitable for orally administered treatment.

    For inclusion in the genetic research component of the study, patients must fulfil the following criterion:

    1. Provision of informed consent for genetic research.
    E.4Principal exclusion criteria
    1. Untreated unstable brain or meningeal metastases. Patients with radiological evidence of stable brain metastases are eligible providing that they are asymptomatic and either:
    a. do not require corticosteroids or
    b. have been treated with corticosteroids, with clinical and radiological evidence of brain metastases stabilisation at least 10 days after discontinuation of steroids.

    2. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count <1.5 x 109/L or platelet count <100 x 109/L or requiring regular blood transfusions to maintain haemoglobin >9 g/dL.

    3. Serum bilirubin >1.5 x upper limit of reference range (ULRR).

    4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x ULRR. If liver metastases are present, ALT or AST >5 x ULRR.

    5. Serum creatinine >1.5 x ULRR or a creatinine clearance of <50mL/min calculated by Cockcroft-Gault.

    6. Greater than +1 proteinuria on 2 consecutive dipsticks taken no less than 1 week apart or if urinary protein >1.5 g in a 24-hour urine collection.

    7. Patients with a history of poorly controlled hypertension with resting BP >150/100 mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy. Measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2 minute intervals and averaged. If the first 2 diastolic readings differ by more than 5 mmHg then an additional reading should be obtained, and averaged.

    8. Patients who are currently receiving maximal doses of calcium-channel blockers or more than 1 anti-hypertensive for the treatment of hypertension.

    9. Any evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated respiratory, cardiac including arrhythmias, hepatic or renal disease), including known infection with Hepatitis B or C virus or human immunodeficiency virus.

    10. Unresolved toxicity >CTC grade 2 from previous anti-cancer therapy except alopecia (if applicable).

    11. Mean QTc with Bazett’s correction >470 msec in screening electrocardiogram (ECG) or history of familial long QT syndrome (as per International Conference on Harmonisation [ICH] guideline E14).

    12. Significant haemorrhage (>30 ml bleeding/episode in previous 3 months) or haemoptysis (>5 ml fresh blood in previous 4 weeks).

    13. Recent (<14 days) major surgery prior to entry into the study, or a surgical incision that is not fully healed.

    14. Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication.

    15. Known severe hypersensitivity to AZD2171 or any of its excipients.

    16. Other concomitant anti-cancer therapy, except steroids or hormone therapy for prostate cancer (eg, Zoladex).

    17. Known severe hypersensitivity to beta-blockers or calcium-channel blockers.

    18. History of other malignancies within 5 years except for adequately treated basal or squamous cell cancer or carcinoma in situ.

    19. History of CNS disorders or uncontrolled seizures.

    20. History of significant gastrointestinal impairment, as judged by the investigator that would significantly affect the absorption of AZD2171.

    21. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff and staff at the study site).

    22. Previous enrolment or randomisation of treatment in the present study.

    23. Participation in an investigational drug trial within 30 days prior to starting AZD2171.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients requiring temporary (>1 day) or permanent withdrawal of AZD2171 prior to progression and within 12 weeks of the first dose of AZD2171. Hypertension is one of the most common AEs reported with AZD2171. Thus, the primary efficacy variable will evaluate whether the application of a hypertension management strategy with or without prophylactic treatment protects patients from the consequences of severe hypertension and minimises dose interruptions and reductions, so as to maximise the potential anti-tumour effects of AZD2171.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Management of AZD2171-induced hypertension to avoid treatment discontinuation
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date 12 weeks after the last patient has entered the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-10-10. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2005-11-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-11-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-04-26
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