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    Summary
    EudraCT Number:2012-002874-30
    Sponsor's Protocol Code Number:008424QM
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-12-27
    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 number2012-002874-30
    A.3Full title of the trial
    AN OPEN LABEL RANDOMISED PHASE II STUDY COMPARING AZD2014 VERSUS EVEROLIMUS IN PATIENTS WITH ADVANCED METASTATIC RENAL CANCER AND PROGRESSION ON VEGF TARGETED THERAPY
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ZEBRA: AZD2014 compared to Everolmus in Renal Cancer
    A.3.2Name or abbreviated title of the trial where available
    ZEBRA
    A.4.1Sponsor's protocol code number008424QM
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01793636
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorQueen Mary University of London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre for Experimental Cancer Medicine, Queen Mary University of London
    B.5.2Functional name of contact pointZEBRA Trial Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressLower Ground floor, Old Anatomy Building, Charterhouse Square
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC1M 6BQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02078828506
    B.5.5Fax number02078825958
    B.5.6E-mailzebra@qmcr.qmul.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharmaceutivcals UK Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameAfinitor
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAZD2014
    D.3.2Product code AZD2014
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Clear Cell Renal Cancer
    E.1.1.1Medical condition in easily understood language
    Kidney Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10050018
    E.1.2Term Renal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 is to investigate if AZD2014 is associated with a delay in progression free survival(PFS)compared to everolimus.
    E.2.2Secondary objectives of the trial
    a)To evaluate tumour response rate after at least 8 weeks of treatment with the study drugs. B) To compare overall survival of the two group of patients. c) To determine the safety profile of AZD2014 and to compare with that of everolimus.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histopathologically confirmed renal cell carcinoma with measurable metastases on CT/MRI imaging. A component of clear cell must be present.

    2. Radiological progressive disease on VEGF targeted therapy (RECIST v1.1). Exposure to more than one line of VEGF targeted therapy is acceptable. Previous treatment with initial interferon,n or IL- 2 prior or another experimental agent is acceptable (with the exception of drugs specifically targeting mTOR).

    3. Evidence of measurable disease (i.e., ≥1 malignant tumour mass that can be accurately measured in at least 1 dimension ≥ 20 mm with conventional computerized tomography ([CT]) scan or Magnetic Resonance Imaging ([MRI]), or ≥10 mm (except lymph nodes which must have short axis ≥ 15 mm) with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable.

    4. Adequate organ function as defined by the following criteria:
    a. Total serum bilirubin ≤1.5 x ULN (patients with Gilbert’s disease exempt),
    b. Serum transaminases ≤3.0 x ULN (x5 in the presence of liver metastasis).
    c. Serum creatinine ≤ 2 x ULN or estimated GFR e.g. Cockcroft and Gault >30ml/min
    d. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support,
    e. Platelets ≥ 100 x 109/L

    5. Signed and dated informed consent document indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment. This includes the collection of archived tissue.

    6. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures

    7. ECOG performance status of 0, 1 or 2.

    8. Life expectance >12 weeks

    9. At least 14 days since the end of prior systemic treatment (e.g. sunitinib, pazopanib, sorafenib or any other approved therapy for renal cancer), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 4.03 grade ≤1 or back to baseline except for alopecia or hypothyroidism. 21 days gap between bevacizumab and INF (interferon) treatment should exist.

    10. Fasting blood sugar ≤8mmol/l and HbA1C ≤7% (equivalent to 53 mmol/mol)

    11. Males and Females of age ≥18 years
    E.4Principal exclusion criteria
    1. Previous exposure to mTOR inhibitors for metastatic renal cancer.

    2. Females of child-bearing potential. The definition of child-bearing potential: women between menarche and menopause who have not been permanently or surgically sterilised and are capable of procreation. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate. Male patients must be surgically sterile or agree to use effective contraception.

    3. Pregnant and Breast feeding women.

    4. Any other severe condition (acute/chronic, medical/psychiatric) or laboratory abnormally which the investigator believes would impart excess risk associated with study participation or study drug administration, or would make the patient inappropriate for entry into this study.

    Specifically the following indications are contraindicated: Hereditary galacto-intolerance, glucose/galactose malabsorbtion and lactose deficiency.

    5. Untreated clinically symptomatic brain or meningeal metastases. Patients with evidence of clinically stable brain metastases are eligible providing that they do not require corticosteroids.

    6. Any evidence of severe or uncontrolled diseases e.g., unstable or uncompensated respiratory, hepatic or renal disease.

    7. Any evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung disease).

    8. Unresolved toxicity ≥ CTCAE (v 4.03) grade 2 (except alopecia and hypothyroidism) from previous anti-cancer therapy.

    9. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ or localised controlled prostate cancer) within 5 years, unless the patient has been disease free for 2 years and there is a tissue diagnosis of the primary cancer of interest from a target lesion.

    10. Uncontrolled diabetes mellitus or hyperlipideamia (> grade 1)

    11. Treatment with an investigational drug (not including TKIs) within 21 days prior to the first dose of therapy. If the investigational drug is a TKI then treatment within 14 days prior to the first dose of therapy.

    12. Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:
    a. Coronary artery bypass graft
    b. Angioplasty
    c. Vascular stent
    d. Myocardial infarction
    e. Angina pectoris
    f. Congestive heart failure new york heart association grade ≥2
    g. Ventricular arrhythmias requiring continuous therapy
    h. Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled
    i. Haemorrhagic or thrombotic stroke, including transient ischaemic attacks or
    j. Any other central nervous system bleeding

    13. Mean resting QTcF ≥ 470 msec as per local reading

    14. Abnormal ECHO at baseline (left ventricular ejection fraction [LVEF] <50%.

    15. Known inherited or acquired immunodeficiency

    16. Known active hepatitis B or C infection or HIV.

    17. Other concomitant anti-cancer therapy (including LHRH agonists)

    18. Previous bone marrow transplant

    19. Male or female aged < 18 years

    20. Any haemopoietic growth factors (eg, G-CSF, GM-CSF) within 2 weeks prior to receiving study drug.
    E.5 End points
    E.5.1Primary end point(s)
    Following patients to progression free survial.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be followed up for 12 months after randomisation.
    E.5.2Secondary end point(s)
    Determining causality of each adverse event (AE) to AZD2014 or Everolimus and grading severity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

    Determination of the time from treatment until death.

    Response assessment (stable disease (SD), partial response (PR) or complete response (CR)) determined according to Response Evaluation Criteria in Solid Tumours (RECIST v 1.1) in all patients receiving at least one cycle of treatment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be followed up for 12 months after randomisation.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned25
    E.8.5The trial involves multiple Member States No
    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 No
    E.8.7Trial has a data monitoring committee Yes
    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’ is defined as the date when all patients have died or have been followed up for at least 12 months after randomisation.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Treating Medical Oncologist will decide on the best treatment options for the participant once their participation has ended in the trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2014-12-31
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