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    Summary
    EudraCT Number:2012-003187-44
    Sponsor's Protocol Code Number:UC-0140/1208
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2014-10-03
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-003187-44
    A.3Full title of the trial
    Randomised, double-blind, multicentre phase III trial evaluating the safety and benefit of adding everolimus to adjuvant hormone therapy in women with high risk of relapse, ER+ and HER2- primary breast cancer who remain free of disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial of everolimus in women with breast cancer
    A.3.2Name or abbreviated title of the trial where available
    UNIRAD V5.0 14/02/2014
    A.4.1Sponsor's protocol code numberUC-0140/1208
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01805271
    A.5.4Other Identifiers
    Name:ICR-CTSUNumber:ICR-CTSU/2013/10042
    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 SponsorUNICANCER
    B.1.3.4CountryFrance
    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 supportPublic program for clinical research
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitute of Cancer Research
    B.5.2Functional name of contact pointDr. Christy Toms
    B.5.3 Address:
    B.5.3.1Street Address15 Cotswold Road
    B.5.3.2Town/ citySutton, Surrey
    B.5.3.3Post codeSM2 5NG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0208 722 4266
    B.5.5Fax number0208 770 7876
    B.5.6E-mailunirad-icrctsu@icr.ac.uk
    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.2.1.1.1Trade name Afinitor
    D.2.1.1.2Name 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 nameEverolimus (Afinitor)
    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.3.9.3Other descriptive nameAfinitor
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number10
    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
    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
    ER+, HER2- early breast cancer
    E.1.1.1Medical condition in easily understood language
    Potentially curable breast cancer which is positive for oestrogen receptor expression and negative for HER2 expression
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057654
    E.1.2Term Breast cancer female
    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 principal research question of the UNIRAD trial is: when everolimus treatment is given to breast cancer patients in addition to their standard care, is the chance of their cancer returning reduced in comparison to patients who did not receive everolimus treatment?
    E.2.2Secondary objectives of the trial
    The secondary research questions of the UNIRAD trial include: when everolimus treatment is given to breast cancer patients in addition to standard care:
    - do patients live longer than patients who did not receive everolimus treatment?
    - is there a certain group of patients who benefit the most from everolimus treatment (both in terms of their cancer returning and how long they live)?
    - is everolimus treatment safe and tolerable for the patients participating in the UNIRAD trial?
    - what can be learned from the biology of the patients' tumour tissue - are there biological markers that identify the patients who benefit most from everolimus treatment?
    - is the quality of life of patients who receive everolimus treatment the same as patients who did not receive everolimus treatment?
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The UNIRAD protocol contains details of two planned sub-studies which are considered integral to the trial design (as they are contained in the protocol, no seperate version numbers are provided):

    - Quality of Life (EORTC QLQ-C30)
    Patients will complete quality of life questionnaires every 4 months while they are receiving trial treatment. The quality of life of patients who received everolimus will be compared to the quality of life of those who did not.

    - Translational sub-studies
    A number of exploratory analyses are planned using tumour and blood samples collected from patients participating in the trial. The aim of these studies will be to investigate which patients are at the highest risk of disease relapse and which patients are most likely to respond to everolimus treatment. A translational sub-study led in the UK will also investigate whether DNA extracted from plasma blood samples (cell free DNA or cfDNA) can be used to determine which patients will respond to treatment and those who are at the highest risk of disease relapse. The collection of blood samples is much less invasive than the collection of tumour tissue, and as such if blood samples are able to provide information which currently is only available from tumour tissue, this will be very important for future research and treatment.
    E.3Principal inclusion criteria
    1. Female ≥ 18 years of age
    2. Histologically proven invasive unilateral or bilateral breast cancer (regardless of the morphological subtype)
    3. Any T, M0 (according to the American Joint Committee on Cancer classification)
    4. At least 4 positive lymph nodes if the patient had primary surgery, or at least 1 positive lymph node if surgery was conducted after neo-adjuvant chemotherapy or hormone therapy of at least 3 months duration
    5. ER+ and HER2 negative : Hormone receptor positive is defined as any staining on the primary tumor, HER2 negativity is defined as IHC 0-1+, or [IHC 2+ and FISH or CISH non-amplified]
    6. Primary tumor completely resected (deep margins and overlying skin involvement allowed if fully resected)
    7. Patients who have received at least 1 year but not more than 4 years of adjuvant hormone therapy. Hormone therapy could be either tamoxifen, letrozole, anastrozole or
    exemestane.
    8. No clinically or radiologically detectable metastases at time of inclusion.
    9. WHO Performance status (ECOG) of 0 or 1.
    10. Adequate hematological function (neutrophil count  2x109/l, platelet count  100x 109/l)
    11. Adequate hepatic function: AST and ALT ≤ 2.5 ULN, alkaline phosphatases ≤ 2.5 ULN, total bilirubin ≤ 2 ULN.
    12. Adequate renal function: serum creatinine ≤ 1.5 ULN.
    13. Signed written informed consent.
    E.4Principal exclusion criteria
    1. Any local, or regional recurrence or metastatic disease.
    2. Any clinical or radiological suspicion of malignant or pre-malignant disease in the contralateral breast.
    3. Previous cancer (excepted basal cell carcinoma of the skin or in situ carcinoma of the cervix) in the preceding 5 years, including invasive contralateral breast cancer.
    4. Patient already included in another ongoing therapeutic trial involving an unlicensed drug for which follow-up is required.
    5. Patient who is pregnant or breast-feeding. Adequate birth control measures should be taken during the study treatment phase.
    6. Patient with significantly impaired lung function (e.g. Chronic Obstructive Pulmonary Disease, respiratory insufficiency, Interstitial Lung Disease)
    7. Positive serology for HIV infection or hepatitis C.
    8. Chronic carrier of HBV (positive Antigen HbsAg positive HbS in the blood)
    9. Patient with chronic infection
    10. Uncontrolled diabetes defined as glycated haemoglobinemia , HbA1c>7%
    11. Uncontrolled hypercholesterolemia (cholesterol >300 mg/dl under adequate therapy).
    12. Known hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.
    13. Patient with other concurrent severe and/or uncontrolled medical disease or infection which could compromise participation in the study (e.g. patient who regularly require systemic steroids to control co-morbid disease).
    14. Patient with any psychological, familial, social or geographical condition which could potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
    15. Patients with pN1mi as sole nodal involvement
    E.5 End points
    E.5.1Primary end point(s)
    Disease free survival rate (DFS) after randomization (disease is defined as local, regional or metastatic relapse, a new contralateral breast cancer, or death from any cause).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Disease Free Survival will be calculated from randomization date to first occurrence of breast cancer relapse (local, regional or distant) or to the date of invasive contralateral breast cancer or death from any cause, whichever occurs first or to date of last visit (censured data).
    E.5.2Secondary end point(s)
    1) Efficacy:
    - Assessment of impact of everolimus on the overall survival (OS), the Event Free Survival (EFS), Distant Metastasis Free Survival (DMFS) and Bone Metastatic Free survival (BMFS)
    - Assessment of impact of everolimus on DFS and OS in ER+,PR+ and ER+/PR subgroups
    - Impact of everolimus on the incidence of secondary cancers

    2) Toxicity:
    - Assessment of the safety profile of everolimus in combination with hormone therapy.

    3) Biological:
    - Predictive value of mTOR activation markers on DFS: IHC analysis of primary tumor for pS6K and p4EBP.
    - Other translational analyses linking cancer biology with outcomes

    4) Quality of life sub-studies
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Efficacy will be assessed for at least 15 years after the end of study (time from when last patient has completed their 5 year follow up)

    2) Toxicity will be assessed for a total of 7 years (2 years whilst the patient is on study treatment, 5 years during follow up)
    YYear 1 - at month 1, month 2, month 3, month 4, month 8, month 12
    Year 2 - month 16, month 20, month 24
    Year 3 - every 6 months
    Year 4 - every 6 months
    Year 5 - yearly
    Year 6 - yearly
    Year 7 - yearly

    3) Biological - samples will be stored indefinately, destroyed after use or returned to the donors hospital, no time point is specified for the analysis of these

    4) Quality of life will be assessed for the 2 years the patient is on trial treatment at baseline, M1, M4, M8, M12, M16, M20, M24.
    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 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) 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 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) No
    E.8.2.2Placebo Yes
    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 concerned23
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA88
    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
    Date of last data capture for the last patient.
    These breast cancer patients remain at risk of relapse for at least another 10 years so long-term follow-up is important for efficacy reasons, and for safety reasons we need to understand any possible late effects from the use of everolimus. Patients will actively be followed up (seen in clinic) for 5 years post trial treatment. They will then be followed up by tracking of their medical records. Patients consent for this will be sought.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years16
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years16
    E.8.9.2In all countries concerned by the trial months0
    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.1.1Number 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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 250
    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 state500
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1984
    F.4.2.2In the whole clinical trial 1984
    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)
    Patients will receive a maximum of 2 years everolimus / placebo treatment. Everolimus will not be available after the trial.

    Patients will be followed up for 5 years after completion of treatment, after which patients will be followed up in clinic according to routine care.
    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 Decision2014-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-01
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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