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    Summary
    EudraCT Number:2008-008698-69
    Sponsor's Protocol Code Number:CRAD001Y2301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-05-08
    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 ConcernedItaly - Italian Medicines Agency
    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.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberCRAD001Y2301
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    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 FARMA
    B.1.3.4CountryItaly
    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 nameeverolimus
    D.3.2Product code RAD001
    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 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.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 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.3.4Pharmaceutical 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.3.8INN - Proposed INNExemestane
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    estrogen receptor positive locally advanced or metastatic breast cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10006187
    E.1.2Term Breast cancer
    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 that is refractory to non-steroidal aromatase inhibitors
    E.2.2Secondary objectives of the trial
    Key Secondary: To compare the two treatment arms with respect to Overall Survival (OS). Other Secondary: -To evaluate the two treatment arms with respect to: -Overall response rate (ORR), -Time to deterioration of ECOG performance status, -Safety, -Changes in Quality of Life (QoL) scores over time, -Clinical benefit rate (CBR). - To summarize time to response and duration of response in the two treatment arms. -To characterize, in a subgroup of patients, the pharmacokinetics of everolimus (Cmin, C2h) when administered in combination with exemestane. -To 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
    1. Adult women (&amp;#8805; 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy. 2. Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer 3. Postmenopausal women. Postmenopausal status is defined either by: Age &amp;#8805; 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 Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression. 4. Disease refractory to non steroidal aromatase inhibitors (NSAI), defined as: 1. Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole or anastrozole, or 2. Progression while on, or within one month of end of letrozole or anastrozole treatment for ABC. Note: Letrozole or anastrozole do not have to be the last treatment prior to randomization. Patients who received one chemotherapy regimen for ABC are allowed. Other prior anticancer therapy, e.g. tamoxifen, fulvestrant are also allowed. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to randomization. 5. Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to randomization. Note: There are no restrictions as to the last systemic therapy prior to randomization. Patients must have recovered to grade 1 from any adverse events (except alopecia) related to prior therapy prior to randomization. 6. Patients must have: 1. At least one lesion that can be accurately measured in at least one dimension &amp;#8805; 20 mm with conventional imaging techniques or &amp;#8805; 10 mm with spiral CT or MRI or 2. bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above. 7. Adequate bone marrow and coagulation function as shown by: Absolute neutrophil count (ANC) &amp;#8805; 1.5 109/L Platelets &amp;#8805; 100 ×109/L Hemoglobin (Hgb) &amp;#8805; 9.0 g/dL INR &amp;#8804; 2 8. Adequate liver function as shown by: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) &amp;#8804; 2.5 ULN (or &amp;#8804; 5 if hepatic metastases are present) Total serum bilirubin &amp;#8804; 1.5 × ULN (&amp;#8804; 3 × ULN for patients known to have Gilbert Syndrome) 9. Adequate renal function as shown by: Serum creatinine &amp;#8804; 1.5 × ULN 10. Fasting serum cholesterol &amp;#8804; 300 mg/dl or 7.75 mmol/L and fasting triglycerides &amp;#8804; 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 11. ECOG Performance Status &amp;#8804; 2 12. Written informed consent obtained before any screening procedure and according to local guidelines.
    E.4Principal exclusion criteria
    1. HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive). 2. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.). 3. Patients who received more than one chemotherapy regimen for ABC. 4. Previous treatment with exemestane or mTOR inhibitors. 5. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin). 6. 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. 7. 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. 8. Currently receiving hormone replacement therapy, unless discontinued prior to randomization. 9. Symptomatic brain or other CNS metastases Previously treated brain metastases are allowed provided the patient is free of symptoms, prior radiotherapy for brain metastasis was more than four weeks before randomization and the dose of corticosteroids is low and stable for at least two weeks prior to randomization. 10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before randomization are allowed in case of previously treated brain metastases (as described in exclusion criteria n 9). 11. Bilateral diffuse lymphangitic carcinomatosis or metastasis of the lung as the only manifestation of disease (>50% of lung involvement), evidence of metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan. 12. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required. 13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin and acetylsalicylic acid or equivalent, as long as the INR is &amp;#8804; 2.0) 14. Any severe and / or uncontrolled medical conditions such as: Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction &amp;#8804;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 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. 15. 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 prohibited concomitant medications in Table 6-6) 16. History of non-compliance to medical regimens 17. 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 progression or death due to 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 No
    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.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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    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
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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 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 state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    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 Decision2009-07-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-12-04
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