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    Summary
    EudraCT Number:2011-000553-23
    Sponsor's Protocol Code Number:GBG66
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-05-03
    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 ConcernedGermany - BfArM
    A.2EudraCT number2011-000553-23
    A.3Full title of the trial
    A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Es wird untersucht, inwieweit bei Patientinnen mit einem erhöhten Risiko (Her2-positiv, Triple-negativ) durch die Hinzunahme von Carboplatin -zusätzlich zur präoperativen Standardbehandlung mit verschiedenen Chemotherapeutika- die Chance für einen weiteren Rückgang des Tumors präoperativ erhöht werden kann und es häufiger zu einer vollständigen Rückbildung des Tumors kommt.
    A.3.2Name or abbreviated title of the trial where available
    GeparSixto
    A.4.1Sponsor's protocol code numberGBG66
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01426880
    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 SponsorGerman Breast Group GBG Forschungsgesellschaft mbH (Sponsor nach GCP)
    B.1.3.4CountryGermany
    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 supportGBG Forschungs GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportCephalon
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportRoche Pharma AG
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportGlaxoSmithKline GmbH & Co.KG
    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 pointGepar Sixto
    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 number+49610274800
    B.5.5Fax number+4961027480440
    B.5.6E-mailGeparSixto@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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameCarboplatin
    D.3.4Pharmaceutical form Concentrate 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 INNCARBOPLATIN
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients with triple-negative breast cancer, patients with HER2-positive early breast cancer
    E.1.1.1Medical condition in easily understood language
    Patients with an illness associated with a very aggressive form of breast cancer. On a positive note they are responsive to chemotherapy but not responding to receptor targeted treatments
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10021976
    E.1.2Term Inflammatory breast cancer stage IV
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10063104
    E.1.2Term Tubular breast cancer stage II
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10065430
    E.1.2Term HER-2 positive breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10022882
    E.1.2Term Invasive ductal breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10028061
    E.1.2Term Mucinous breast cancer stage II
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10006188
    E.1.2Term Breast cancer female NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10063105
    E.1.2Term Tubular breast cancer stage III
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10021974
    E.1.2Term Inflammatory breast cancer
    E.1.2System Organ Class 100000004864
    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 pathological complete response (pCR=ypT0 ypN0) rates of neoadjuvant treatment of combined cytotoxic-targeted therapy with or without carboplatin in patients with HER2-positive or triple-negative early breast cancer
    E.2.2Secondary objectives of the trial
    •pCR rates per arm
    •toxicity and compliance
    •Comparison of efficacy and tolerability of the carboplatin given at AUC 2.0 or 1.5
    •response rates of the breast tumor and axillary nodes based on physical examination and sonography, mammography or MRI, after treatment in both arms
    •rates of ypT0/is ypN0; ypT0; ypT0/is; ypN0; and regression grades
    •breast and axilla conservation rate after each treatment
    •LRRFS, RRFS, LRFS, DDFS, IDFS and overall survival in both arms
    •pCR rate and LRFS in patients with a clinical complete response and a negative core biopsy before surgery
    •response (complete vs. partial vs. no change) measured by best appropriate imaging method after the first two cycles of treatment with pCR
    •pCR rate in patients with a cCR and a negative core biopsy before surgery
    •RRFS in patients with initial node-positive axilla converted to negative at surgery and treated with sentinel node biopsy alone
    •examine and compare pre-specified molecular markers
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    •CTC / CEC – a laboratory substudy linked to GeparSixto
    •SNPS
    •Surgical substudy in patients with high probability for pCR
    •Substudy on ovarian function
    E.3Principal inclusion criteria
    1.Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
    2.Complete baseline documentation must be submitted via Medcodes® and approved by GBG Forschungs GmbH.
    3.Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
    4.Tumor lesion in the breast with a palpable size of ≥ 2 cm or a sonographical size of ≥ 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
    5.Patients should be in the following stages of disease:
    - cT2 - cT4a-d or
    - cT1c and cN+ or pNSLN+
    6.In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
    7.Centrally confirmed ER/PR/HER-2 and Ki-67 status detected on core biopsy. ER/PR positive is defined as >1% stained cells and HER2-positive is defined as HercepTest IHC 3+ or FISH ratio ≥2.2. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization (4 cores and up to 8-10mm FFPE tumor need to be provided).
    8.Age ≥ 18 years.
    9.Karnofsky Performance status index ≥ 80%.
    10.Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. LVEF must be ≥ 55%.
    11.Laboratory requirements:
    Hematology
    - Absolute neutrophil count (ANC) ≥ 2.0 x 109 / L and
    - Platelets ≥ 100 x 109 / L and
    - Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L)
    Hepatic function
    -Total bilirubin < 1.5x UNL and
    - ASAT (SGOT) and ALAT (SGPT) ≤ 1.5x UNL and
    - Alkaline phosphatase ≤ 2.5x UNL.
    Renal function
    - Creatinine ≤ 175 µmol/L (2 mg/dL) < 1.5x UNL
    - Proteinuria: Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis should undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours.
    If creatinine is between 140 – 175 umol/L (1.6-2.0 mg/dL), the creatinine clearance (calculated or measured) should be ≥ 45 mL/min.
    12.Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
    13.Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound (≤ 21 days), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case of positive bone scan, bone X-ray (or CT or MRI) is mandatory. Other tests may be performed as clinically indicated.
    14.Patients must be available and compliant for central diagnostics, treatment and follow-up.
    E.4Principal exclusion criteria
    1.Prior chemotherapy for any malignancy.
    2.Prior radiation therapy for breast cancer.
    3.Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
    4.Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based chemotherapy).
    5.Previous malignant disease without being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
    6.Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >160 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
    7.Previous thromboembolic event (except when thrombophily screening is negative).
    8.Known hemorrhagic diathesis or coagulopathy with increased bleeding risk.
    9.History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
    10.Pre-existing motor or sensory neuropathy of a severity ≥ grade 2 by NCI-CTC criteria v 4.0.
    11.Currently active infection.
    12.Active peptic ulcer.
    13.Incomplete wound healing or unhealed bone fracture.
    14.Disease significantly affecting gastrointestinal function, e.g. malabsorption syndrome, resection of the stomach or small bowel, ulcerative colitis.
    15.History of abdominal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment.
    16.Severe pulmonary condition / illness.
    17.Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment with bevacizumab. No minor surgeries including insertion of an indwelling catheter or sentinel lymph node biopsy within 24 h prior to chemotherapy.
    18.Definite contraindications for the use of corticosteroids except inhalative corticoids.
    19.Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol;
    20.Concurrent treatment with:
    - chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 10 mg methylprednisolone or equivalent).
    - sex hormones. Prior treatment must be stopped before study entry.
    - virostatic agents like sorivudine or analogs like brivudine, concurrent treatment with aminoglycosides.
    - anticoagulants: heparin, warfarin as well as acetylic acid (e.g. Aspirin®) at a dose of > 325 mg/day or clopidogrel at a dose of > 75 mg/day.
    - other experimental drugs or any other anti-cancer therapy.
    - drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A, e.g. Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Ritonavir, Telithromycin, Erythromycin, Verapamil, Diltiazem within the last 5 days or the expected need for these treatments during study participation.
    21.Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
    22.Male patients.
    E.5 End points
    E.5.1Primary end point(s)
    Pathological complete response of breast and lymph nodes (ypT0 ypN0; primary endpoint)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries. Surgery takes place shortly after the 18 weeks (six 3-week cycles) chemotherapy treatment
    E.5.2Secondary end point(s)
    1.ypT0/is ypN0; ypT0; ypT0/is; ypN0, and regression grade, response by physical examination, imaging response, breast conservation
    2. Clinical (c) and imaging (i) response will be assessed by physical examination and imaging tests.
    3. loco-regional invasive recurrence free survival (LRRFS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS)
    4. Tolerability and Safety: Descriptive statistics for the 4 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped
    5. Translational research: Exploratory analyses will be performed to identify possible relationships between biomarkers and drug activity.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Clinical (c) and imaging (i) response will be assessed in the 3rd week of cycle 2 (week 6) and cycle 6 (week 18) by physical examination and imaging tests.
    2. in the 3rd week of cycle 2 and cycle 6
    3. LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event
    4. throughout the 18 weeks treatment period and the 30 day safety follow up
    5. with core examination and with surgery. In addition and optional after 2nd cycle, before and after surgery
    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 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 concerned80
    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 this study is defined as 1 months after the last patient had surgery (not considering patients in which no surgery is planned or possible)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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.1.1.2Preterm 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: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 600
    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 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 state600
    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)
    As no study specific treatment or investigation is planned after surgery, follow up is not part of this study. However, information on the health status of the patients is collected either based on yearly chart reviews at the sites or based on information deriving from the GBG registry of previous study participants.

    Her2 positive patients only will continue the treatment with lapatinib after surgery. If they are in addition HR-positive they will receive an additional adequate treatment.
    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 Decision2011-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-09-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-07-30
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