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    Summary
    EudraCT Number:2006-003695-35
    Sponsor's Protocol Code Number:D4200C00036
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-11-23
    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 ConcernedGermany - BfArM
    A.2EudraCT number2006-003695-35
    A.3Full title of the trial
    A Phase III, Randomized, Double-blinded, Parallel Group, Multi-centre
    Study to Assess the Efficacy and Safety of ZD6474 (ZACTIMA™) in
    Combination with Pemetrexed (Alimta®) versus Pemetrexed alone in
    Patients with Locally-Advanced or Metastatic (stage IIIB or IV) Non-Small
    Cell Lung Cancer (NSCLC) after Failure of 1st Line Anti-cancer Therapy
    A.4.1Sponsor's protocol code numberD4200C00036
    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 No
    D.2.5.1Orphan drug designation number
    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 Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name ALIMTA
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland BV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.1Product namepemetrexed
    D.3.4Pharmaceutical form Intravenous infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpemetrexed
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Locally-advanced or Metastatic (stage IIIB or IV) Non-Small Cell Lung Cancer (NSCLC).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10029514
    E.1.2Term Non-small cell lung cancer NOS
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to demonstrate an improvement in PFS as assessed by RECIST criteria, for the combination of ZD6474 plus pemetrexed (Alimta®) compared with pemetrexed plus placebo in patients with locally advanced or metastatic NSCLC after failure of 1st line anti-cancer therapy (not including an adjuvant regimen).
    E.2.2Secondary objectives of the trial
    Demonstrate improvement in overall survival for ZD6474 in combination with pemetrexed compared with pemetrexed plus placebo
    Demonstrate an improvement in the overall objective response rate (ORR) (complete response [CR] + partial response [PR]), disease control rate (DCR) (CR + PR + stable disease [SD] ≥ 6 weeks) and duration of response (DOR), assessed by RECIST criteria
    Demonstrate a beneficial effect on disease-related symptoms, based on the Lung Cancer Symptom Scale (LCSS)
    Demonstrate an improvement in time to deterioration of disease-related symptoms (TDS)
    To study the tolerability and safety of ZD6474 in combination with pemetrexed by assessment of AEs, clinically significant laboratory or vital signs abnormalities and ECG changes
    Investigate the population pharmacokinetics (PK) of ZD6474 in this patient population and assess the PK-QTc relationship, PK-safety relationship, PK-efficacy relationship and PK-PD relationship by evaluation of appropriate PK parameters
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of informed consent
    2. Female or male aged 18 years or above
    3. Histologic or cytologic confirmation of locally advanced or metastatic NSCLC (stage IIIB or IV) on entry into study
    4. Failure of 1st line anti-cancer therapy (either radiological documentation of disease progression or due to toxicity) or subsequent relapse of disease following 1st line therapy
    5. WHO Performance status 0 - 2
    6. One or more measurable lesions at least 10 mm in the longest diameter (LD) by spiral CT scan or 20 mm with conventional techniques according to RECIST criteria. Previously irradiated lesions will not be considered measurable.
    7. Life expectancy of 12 weeks or longer
    8. Negative pregnancy test for women of childbearing potential only

    For inclusion in this genetic research, patients must fulfil the following criterion:
    1. Provision of informed consent for the genetic research
    2. Provision of informed consent for tissue research
    E.4Principal exclusion criteria
    1. Mixed small cell and non-small cell lung cancer histology
    2. Patients have received 2nd-line or subsequent anti-cancer therapy
    3. Prior treatment with pemetrexed
    4. Prior treatment with VEGFR TKIs (previous treatment with bevacizumab [Avastin] is permitted)
    5. Known or suspected brain metastases or spinal cord compression, unless treated at least 4 weeks before entry, and stable without steroid treatment for 10 days
    6. The last radiation therapy within 4 weeks before the start of study therapy, not including local palliative radiation
    7. The last dose of prior chemotherapy or other anti-cancer therapy is discontinued less than 3 weeks before the start of study therapy (6 weeks for nitrosoureas, mitomycin, and suramin)
    8. Major surgery within 4 weeks before entry, or incompletely healed surgical incision
    9. Neutrophils <1.5 x 109/L or platelets <100 x 109/L
    10. Serum bilirubin >1.5 x the upper limit of reference range (ULRR)
    11. Creatinine clearance <50 ml/min calculated by either Cockcroft -Gault, 24 hours urine collection, EDTA scan or other validated methods.
    12. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x ULRR in the absence of liver metastases, or > 5 x ULRR in the presence of liver metastases
    13. Alkaline phosphatase (ALP) >2.5 x ULRR in the absence of liver metastases, or >5 x ULRR in the presence of liver metastases
    14. Current active gastrointestinal disease that may affect the ability of the patient to absorb ZD6474 or tolerate diarrhoea
    15. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol
    16. Any unresolved toxicity greater than CTCAE Grade 2 from previous anti-cancer therapy
    17. Significant cardiovascular event (e.g., myocardial infarction, superior vena cava [SVC] syndrome), New York Heart Association [NYHA] classification of heart disease > 2 within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
    18. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded
    19. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
    20. QT prolongation with other medications that required discontinuation of that medication
    21. Presence of left bundle branch block (LBBB)
    22. QTc with Bazett’s correction unmeasurable or ≥ 480 msec on screening ECG (Note: If a patient has QTc interval ≥ 480 msec on screening ECG, the screen ECG may be repeated twice [at least 24 hours apart]. The average QTc from the three screening ECGs must be <480 msec in order for the patient to be eligible for the study) Patients who are receiving a drug that has a risk of QTc prolongation (see Appendix D, Table 2) are eligible if QTc is <460 msec.
    23. Potassium <4.0 mmol/L despite supplementation; serum calcium (or ionized or adjusted for albumin), or magnesium out of normal range despite supplementation.
    24. Women who are pregnant or breast feeding
    25. Any concomitant medications that may cause QTc prolongation or induce Torsades de Pointes (see Appendix D for the lists of medications in Table 1 & Table 2) or induce CYP3A4 function (see Section 3.7.2). Drugs listed in Appendix D, Table 2,
    that in the investigator’s opinion cannot be discontinued, are allowed, but only of
    the QTc is <460 msec
    26. Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 millimetre of mercury [mmHg] or diastolic blood pressure greater than 100 mmHg)
    27. Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin
    28. Treatment with a non-approved or investigational drug within 30 days before Day 1 of study treatment
    29. Concomitant use of yellow fever vaccine or any live attenuated vaccines
    30. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site).
    31. Patients of Japanese origin
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome variable:
    - Improvement in progression-free survival (PFS) for the combination of ZD6474 plus pemetrexed (Alimta®) compared with pemetrexed plus placebo.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    The end of study will be declared once a program has been established for remaining patients still receiving ZD6474 study treatment after the final analysis of this trial has occurred.
    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 months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 178
    F.4.2.2In the whole clinical trial 510
    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 Decision2006-12-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-12-22
    P. End of Trial
    P.End of Trial StatusCompleted
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