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    The EU Clinical Trials Register currently displays   39564   clinical trials with a EudraCT protocol, of which   6487   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2008-008698-69
    Sponsor's Protocol Code Number:CRAD001Y2301
    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:2009-05-22
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2008-008698-69
    A.3Full title of the trial
    A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination with Exemestane in the Treatment of Postmenopausal Women with Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer who are refractory to Letrozole or Anastrozole.
    A.4.1Sponsor's protocol code numberCRAD001Y2301
    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 SponsorNovartis Pharma Services AG
    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 supportNovartis Pharma Services AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharmaceuticals UK Ltd
    B.5.2Functional name of contact pointMedical Information Services
    B.5.3 Address:
    B.5.3.1Street AddressFrimley Business Park, Frimley
    B.5.3.2Town/ cityCamberley, Surrey
    B.5.3.3Post codeGU16 7SR
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number441276 698370
    B.5.5Fax number441276698449
    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 Yes
    D. name Afinitor
    D. of the Marketing Authorisation holderNovartis Europharm Limited
    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 nameRAD001 5mg Tablets (elongated)
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor codeRAD001
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term Breast cancer
    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
    To compare the combination treatment of everolimus and exemestane to exemestane alone with respect to progression-free survival in postmenopausal women with estrogen receptor positive breast cancer refractory to NSAIs.
    E.2.2Secondary objectives of the trial
    Key Secondary Objective
    ▪To compare overall survival (OS) between the 2 treatment arms

    Other Secondary Objectives
    ▪To evaluate the two treatment arms with respect to
    ▫Overall response rate (ORR)
    ▫Time to deterioration of ECOG Performance Status
    ▫Change in QoL scores over time
    ▫Clinical benefit rate (CBR)

    ▪To summarize time to response and duration of response in the two treatment

    ▪Both everolimus and exemestane are substrates of CYP3A4 and there is a
    potential DDI between the two drugs. The study will therefore,
    ▫characterize, in a subgroup of patients, the pharmacokinetics of everolimus
    (Cmin, C2h) when administered in combination with exemestane.
    ▫compare the two treatment arms with respect to pre-dose concentration (Cmin)
    and concentration at 2 hours post dose (C2h) of exemestane and to compare, in
    a subgroup of patients, the two treatment arms with respect to estradiol (E2)
    changes from baseline.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Please see protocol for full list and details
    ▪Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer
    not amenable to curative treatment by surgery or radiotherapy.
    ▪ Histological or cytological confirmation of estrogen-receptor positive (ER+) breast
    ▪ Postmenopausal women. Postmenopausal status is defined either by:
    ▫ Age ≥ 55 years and one year or more of amenorrhea
    ▫ Age < 55 years and one year or more of amenorrhea, with an estradiol assay <
    20 pg/ml
    ▫ Surgical menopause with bilateral oophorectomy.
    ▪ Disease refractory to non steroidal aromatase inhibitors (NSAI), defined as:
    ▫ Recurrence while on, or within 12 months of end of adjuvant treatment with
    letrozole or anastrozole, or
    ▫ Progression while on, or within one month of end of letrozole or anastrozole
    treatment for locally advanced or metastatic breast cancer (ABC).
    ▪ Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to randomization.
    ▪ Patients must have:
    ▫ At least one lesion that can be accurately measured in at least one dimension ≥
    20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI or
    ▫ bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable
    disease as defined above.
    ▪ Adequate bone marrow and coagulation function as shown by:
    ▫ Absolute neutrophil count (ANC) ≥ 1.5x10 9/L
    ▫ Platelets ≥ 100 ×10 9/L
    ▫ Hemoglobin (Hgb) ≥ 9.0 g/dL
    ▫ INR ≤ 2
    ▪ Adequate liver function as shown by:
    ▫ Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤
    2.5 ULN (or ≤ 5 if hepatic metastases are present)
    ▫ Total serum bilirubin ≤ 1.5 × ULN (≤ 3 x ULN for patients known to have Gilbert Syndrome)
    ▪ Adequate renal function as shown by:
    ▫ Serum creatinine ≤ 1.5 × ULN
    ▪ Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤
    2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can
    only be included after initiation of statin therapy and when the above mentioned
    values have been achieved
    ▪ ECOG Performance Status ≤ 2
    ▪ Written informed consent obtained before any trial related activity and according to local guidelines.
    E.4Principal exclusion criteria
    Please see protocol for full list and details
    ▪ HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ
    hybridization positive).
    ▪ Patients with only non-measurable lesions other than bone metastasis (e.g. pleural
    effusion, ascites etc.).
    ▪ Patients who received more than one chemotherapy line for ABC.
    ▪ Previous treatment with exemestane or mTOR inhibitors.
    ▪ Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
    ▪ Another malignancy within 5 years prior to randomization, with the exception of
    adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell
    carcinoma or non-melanomatous skin cancer.
    ▪ Radiotherapy within four weeks prior to randomization except in case of localized
    radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can
    then be completed within two weeks prior to randomization. Patients must have
    recovered from radiotherapy toxicities prior to randomization.
    ▪ Currently receiving hormone replacement therapy, unless discontinued prior to
    ▪ History of brain or other CNS metastases
    • Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry except in cases outlined below:
    Topical applications, inhaled sprays, eye drops or local injections are allowed.
    Patients on stable low dose of corticosteroids for at least two weeks before randomization are allowed.
    ▪ Bilateral diffuse lymphangitic carcinomatosis.
    ▪ Patients with a known history of HIV seropositivity. Screening for HIV infection at
    baseline is not required.
    ▪ Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose
    warfarin, LMWH and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0)
    ▪ Any severe and / or uncontrolled medical conditions such as:
    ▫ Unstable angina pectoris, symptomatic congestive heart failure, myocardial
    infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia
    ▫ Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
    ▫ Acute and chronic, active infectious disorders (except for Hep B and Hep C positive patients) and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
    ▫ Impairment of gastrointestinal function or who have gastrointestinal disease that
    may significantly alter the absorption of study drugs (e.g., ulcerative disease,
    uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
    ▫ Active skin, mucosa, ocular or GI disorders of Grade > 1
    ▫ Significant symptomatic deterioration of lung function. If clinically indicated,
    pulmonary function tests including measures of predicted lung volumes, DLco, O2
    saturation at rest on room air should be considered to exclude restrictive
    pulmonary disease, pneumonitis or pulmonary infiltrates.
    ▪ Patients being treated with drugs recognized as being strong inhibitors or inducers
    of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole,
    Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to
    randomization (List of clinically relevant drug interaction listed in Tables 6-8 and 6-9)

    • History of noncompliance to medical regimens
    • Patients unwilling to or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    progression-free survival (PFS), defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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. 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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA72
    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 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 visit is the date when no further patient information will be collected, including reasons for death or lost to follow-up. It occurs after the last survival information is collected.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days3
    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 No
    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 Yes
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    please refer to protocol section 11 "Administrative procedures", subsection "Informed Consent"
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 343
    F.4.2.2In the whole clinical trial 705
    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 Decision2009-06-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-08-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-12-04
    The status of studies in GB is no longer updated from 1.1.2021
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