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    Summary
    EudraCT Number:2004-002355-14
    Sponsor's Protocol Code Number:GBG36
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-11-22
    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 ConcernedAustria - BASG
    A.2EudraCT number2004-002355-14
    A.3Full title of the trial
    A randomized, multicenter, open phase III study comparing the postoperative use of
    zoledronic acid versus no treatment in patients with histological tumor residuals after preoperative anthracycline and taxane containing chemotherapy for primary breast cancer (NEO-ADJUVANT TRIAL ADD-ON)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neo-Adjuvant Trial Add-On
    A.3.2Name or abbreviated title of the trial where available
    NATAN
    A.4.1Sponsor's protocol code numberGBG36
    A.5.4Other Identifiers
    Name:ABCSGNumber:ABCSG 29
    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 SponsorGBG Forschungsgesellschaft mbH
    B.1.3.4CountryGermany
    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
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGBG Forschungs GmbH
    B.5.2Functional name of contact pointClinical Project Manager
    B.5.3 Address:
    B.5.3.1Street AddressMartin Behaim Strasse 12
    B.5.3.2Town/ cityNeu-Isenburg
    B.5.3.3Post code63263
    B.5.3.4CountryGermany
    B.5.4Telephone number4961027480337
    B.5.5Fax number4961027480440
    B.5.6E-mailioannis.gkantiragas@germanbreastgroup.de
    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 Zometa®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm, Horsham, UK
    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 namezoledronic acid
    D.3.2Product code CGP 42446
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNZOLEDRONIC ACID
    D.3.9.1CAS number 118072-93-8
    D.3.9.4EV Substance CodeSUB00176MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 Yes
    D.2.1.1.1Trade name Femara®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma GmbH, Wien
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 nameletrozole
    D.3.4Pharmaceutical form Film-coated 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 INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with histological tumor residuals after preoperative anthracycline and taxane containing chemotherapy for primary breast cancer
    E.1.1.1Medical condition in easily understood language
    breast cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - to determine the event-free survival (EFS) after zoledronic acid for 5 years versus no postoperative treatment in patients with “chemo-insensitive” breast cancer (ypT1-4 and/or ypN1-3) after preoperative anthracycline/taxane containing chemotherapy
    E.2.2Secondary objectives of the trial
    - to determine overall survival in both treatment arms
    - to determine the EFS with respect to the interval between surgery and randomization
    - to determine the bone-metastasis free-survival in both arms
    - to determine the toxicity of and compliance to zoledronic acid
    - to determine the predictive value of primary breast tumor response on the effect of postoperative treatment
    - to determine the prognostic impact of chemotherapy induced amenorrhea in premenopausal patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures;
    - Complete baseline documentation sent to GBG;
    - Prior preoperative chemotherapy for at least 4 cycles, of which at least two must contain a taxane and an anthracycline given within a clinical trial approved by the protocol board;
    - Completely resected unilateral or bilateral primary carcinoma of the breast with histologically detectable tumor residuals (ypT1-4) and or histologically confirmed involvement of axillary nodes (ypN1-3). Complete axillary clearance is mandatory, sentinel node biopsy alone is not allowed in node positive cases;
    - A maximum interval from date of axillary surgery to entering this trial of 3 years;
    - Age 18 years or older;
    - Karnofsky index >= 70%;
    - Life expectancy of at least 10 years, disregarding the diagnosis of cancer;
    - No clinical evidence of local recurrence or distant metastases. Complete staging work-up within 3 months prior to registration. All patients must have (bilateral) mammography or breast MRI, breast ultrasound, chest X-ray, ultrasound or CT scan of the liver, and bone scan (within 8 months). In case of a positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated;
    - Adequate renal and hepatic function (serum creatinine, bilirubin, and transaminases within 1.5 × upper normal range);
    - Tissue block centrally available for further biological tests;
    - Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating center.
    E.4Principal exclusion criteria
    - Known hypersensitivity reaction to the investigational compound;
    - Prior postoperative chemotherapy;
    - Prior treatment with bisphosphonates since breast cancer surgery;
    - Pregnant or lactating patients. Patients of childbearing potential must have a negative pregnancy test (urine or serum) within 14 days prior to registration and must implement adequate non-hormonal contraceptive measures during study treatment;
    - History of diseases with influence on bone metabolism, such as Paget’s disease of bone and primary hyperparathyroidism or osteoporosis requiring treatment at the time of study entry or considered likely to become necessary within the six months
    - Other serious illness or medical condition that may interfere with the understanding and giving of informed consent and the conduct of the study
    - Prior or concomitant secondary malignancy (except non-melanomatous skin cancer or carcinoma in situ of the uterine cervix)
    - Concurrent treatment with other experimental drugs or any other anti-cancer therapy;
    - Serum creatinine >= 3 mg/dl (265 micromol/L)
    - Corrected (adjusted for serum albumin) serum calcium concentration < 8.0 mg/dl (2.00 mmol/L) or >= 12.0 mg/dl (3.00 mmol/L)
    - Concurrent treatment with sex hormones. Prior treatment must be stopped before study entry;
    - Male patients.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this trial is to show that zoledronic acid will prolong the event-free survival (EFS) compared to no postoperative adjuvant treatment. The following assumptions are made:
    - According to the results published by Kuerer et al. on the EFS of
    patients with remaining tumor (ypT1-T4) in the breast and positive lymph
    nodes after preoperative chemotherapy, the EFS at 5 years is postulated
    to be 58%.
    - There will be an improvement of the hazard ratio of 37% to an EFS of 67.2 % for patients receiving zoledronic acid
    - The error rate for a false positive outcome () is set to 5%, using two-sided significance tests
    - The error rate for a false negative outcome () is set to 20%, i.e. the power of the trial is set to 80% for the difference of clinical interest
    - A common exponential drop-out rate of 5%
    - Accrual period of 48 months during which patients enter the study
    - Follow-up period from the end of accrual until the analysis of the data: approx. 48 months.
    - Randomization will be stratified according to the participating center, time interval between surgery and entering this trial (within 3 months, within 1 year, within 2 years, within 3 years).
    The total number of patients required for the trial is equal to 654 (i.e. 327 patients per arm) to observe a total number of 316 events with the end of follow up.
    Stratification factor:
    - Receptor status (ER and / or PgR pos. vs. ER and PR neg.)
    - Time since surgery (0-3 vs. 4-12 vs. 12-24 vs. 24-36 months)
    - Age (< 50 vs. ≥ 50 years at study entry)
    - Center
    E.5.1.1Timepoint(s) of evaluation of this end point
    the time to first breast cancer event which is defined as time from randomization to (histological) diagnosis of first local, regional, contralateral or
    distant recurrence, secondary primary or death due to any cause
    E.5.2Secondary end point(s)
    - to determine overall survival (OS) in both treatment arms
    - to determine the EFS with respect to the interval between surgery and randomization
    - to determine the bone-metastasis free-survival in both arms
    - to determine the toxicity of and compliance to
    zoledronic acid
    - to determine the predictive value of primary breast tumor response on the effect of postoperative treatment
    - to determine the prognostic impact of
    chemotherapy induced amenorrhea in
    premenopausal patients
    E.5.2.1Timepoint(s) of evaluation of this end point
    - OS: the interval between the date of randomization and the date of death due to any cause
    - EFS: interval between surgery and randomization
    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 No
    E.6.5Efficacy No
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    observation
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    Enrollment start: December 2004
    Enrollment stop: June 2009
    Interim analysis: After 50% of the required number of events
    Final analysis: After 100 % of the required number of events (approx. 2013)
    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 months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months11
    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.1.1.1In 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.1.2.1Number of subjects for this age range: 654
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 654
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2007-11-22. Yes
    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 state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 654
    F.4.2.2In the whole clinical trial 654
    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)
    Follow up period: 5 years
    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 Decision2007-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-11-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-12-13
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