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    Summary
    EudraCT Number:2005-005077-29
    Sponsor's Protocol Code Number:D4200C00058
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-05-21
    Trial 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 ConcernedCzechia - SUKL
    A.2EudraCT number2005-005077-29
    A.3Full title of the trial
    An International, Phase II, Randomized, Double-Blinded, Placebo-Controlled, Multi-Center Study to Assess the Efficacy of ZD6474 (ZACTIMA ) versus Placebo in Subjects with Unresectable Locally Advanced or Metastatic Medullary Thyroid Cancer.
    A.4.1Sponsor's protocol code numberD4200C00058
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/05/344
    D.3 Description of the IMP
    D.3.1Product nameZACTIMA
    D.3.2Product code ZD6474
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNvandetanib
    D.3.9.2Current sponsor codeZD6474
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 No
    D.3.11.8Extractive medicinal product No
    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 No
    D.IMP: 2
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/05/344
    D.3 Description of the IMP
    D.3.1Product nameZACTIMA
    D.3.2Product code ZD6474
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNvandetanib
    D.3.9.2Current sponsor codeZD6474
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 No
    D.3.11.8Extractive medicinal product No
    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 No
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Medullary thyroid cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10027105
    E.1.2Term Medullary thyroid cancer
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate an improvement in progression-free survival (PFS) with ZD6474 as compared to placebo in subjects with unresectable locally advanced or metastatic MTC
    E.2.2Secondary objectives of the trial
    1. To demonstrate an improvement in the overall objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) with ZD6474 as compared to placebo
    2. To demonstrate an improvement in the overall survival (OS) in subjects with MTC who have been treated with ZD6474 as compared to placebo
    3. To demonstrate an improvement in biochemical response with ZD6474 as compared to placebo as measured by calcitonin (CTN) and carcinoembryonic antigen (CEA)
    4. To demonstrate an increase in the time to opioid analgesic use (TTOU) in subjects who are not taking opioid analgesics at baseline, defined as <10 mg morphine sulfate (or equivalent), with ZD6474 as compared to placebo
    5. To demonstrate a reduction in the use of opioid analgesic medication in subjects with MTC who have pain at baseline requiring ≥10mg/day morphine sulfate or equivalent after treatment with ZD6474 as compared to placebo

    PLUS other secondary and exploratory objectives detailed in the protocol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of written informed consent
    2. Female or male aged 18 years and over
    3. Previously confirmed histological diagnosis of unresectable, locally advanced or metastatic hereditary or sporadic MTC. Documentation must be provided in subject’s medical chart.
    4. Life expectancy of 12 weeks or longer
    5. WHO Performance status 0-2
    6. Able to swallow study medication
    7. Presence of a measurable tumor as defined by:
    a) a solitary lesion measuring ≥2 cm, OR
    b) for multiple lesions, a sum of diameter ≥2cm (with no target lesion measuring <1cm and assuming 5 mm section), OR
    c) for multiple lesions, a sum of diameter ≥3cm (with no target lesion measuring <1.5 cm assuming >5 mm section)
    8. CTN ≥ 500 pg/ml
    9. All subjects (other than those with hereditary MTC who have a documented germline RET mutation) must submit a suitable archived tumor collection sample. If an archived tumor sample is not available prior to 2 weeks of randomization, a fresh tumor sample must be obtained in its place. The tumor sample must be obtained by the investigative site and shipped to its destination prior to randomization.
    10. Negative pregnancy test for female subjects of childbearing potential
    E.4Principal exclusion criteria
    1. Brain metastases or spinal cord compression, unless treated at least 4 weeks before first dose and stable without steroid treatment for 10 days
    2. Any concomitant medications that may affect QTc or induce CYP3A4 function (with the exception of somatostatin or somatostatin analog) and/or any prohibited medications referenced in the protocol3. Major surgery within 4 weeks before randomization
    4. The last dose of prior chemotherapy is received less than 4 weeks prior to randomization
    5. Radiation therapy within the last 4 weeks prior to randomization (with the exception of palliative radiotherapy)
    6. Serum bilirubin greater than 1.5 x the upper limit of reference range (ULRR)
    7. Serum creatinine >1.5 x ULRR or creatinine clearance ≤50 ml/minute (calculated by Cockcroft-Gault formula)
    8. Potassium <4.0 mmol/L despite supplementation; serum calcium (ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
    9. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 x ULRR, or greater than 5.0 x ULRR if judged by the investigator to be related to liver metastases
    10. Significant cardiac event (eg myocardial infarction), superior vena cava [SVC] syndrome, New York Heart Association [NYHA] classification of heart disease ≥2 within 12 weeks before randomization, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
    11. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
    12. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
    13. QT prolongation with other medications that required discontinuation of that medication
    14. Presence of left bundle branch block (LBBB)
    15. QTc with Bazett’s correction unmeasurable or ≥480 msec or greater on screening ECG (Note: If a subject has QTc interval ≥480 msec on screening ECG, the screening ECG may be repeated 2 times [at least 24 hours apart] for a total of 3 ECGs. The average QTc from the three screening ECGs must be <480 msec in order for the subject to be eligible for the study.)
    16. Hypertension not controlled by medical therapy (systolic BP greater than 160 millimeter of mercury [mmHg] or diastolic blood pressure greater than 100 mmHg)
    17. Previous or current malignancies of other histologies within the last 5 years, with the exception of tumors associated with MEN2a and MEN2b, in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin
    18. Any unresolved chronic toxicity greater than CTCAE grade 2 from previous anticancer therapy
    19. Participation in a clinical study and/or receipt of an investigational drug during the last 30 days (participation in the survival follow-up period of a study is not an exclusion)
    20. Previous exposure to ZD6474
    21. Currently pregnant or breast feeding
    22. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site)
    23. Previous randomization or treatment in the present study
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival
    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 No
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    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.8.5.1Number of sites anticipated in the EEA29
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee No
    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
    Subjects who continue to receive ZD6474 study treatment will receive open label supplies for as long as the investigator determines they are obtaining clinical benefit, or until they are given another anti-cancer therapy other than the study medication.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 111
    F.4.2.2In the whole clinical trial 232
    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 Decision2007-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-08-01
    P. End of Trial
    P.End of Trial StatusCompleted
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