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    Summary
    EudraCT Number:2017-000676-29
    Sponsor's Protocol Code Number:BOOG-2017-01
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-11-01
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-000676-29
    A.3Full title of the trial
    Tailoring neoadjuvant therapy in hormone receptor positive, HER2 negative, luminal breast cancer.
    Neoadjuvante therapie op maat in hormoon receptor positieve, HER2 negatieve, luminale borstkanker.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tailored therapy, before surgery, in women after the menopause with hormone sensitive breast cancer.
    Therapie op maat, voorafgaand aan de operatie, bij vrouwen na de overgang met hormoongevoelige borstkanker.
    A.3.2Name or abbreviated title of the trial where available
    NEOLBC study
    NEOLBC studie
    A.4.1Sponsor's protocol code numberBOOG-2017-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03283384
    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 SponsorBOOG Study Center
    B.1.3.4CountryNetherlands
    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 supportPhilips
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportNovartis
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointDr. J.R. Kroep
    B.5.3 Address:
    B.5.3.1Street AddressP.O. Box 9600
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2300 RC
    B.5.3.4CountryNetherlands
    B.5.4Telephone number00310715263464
    B.5.6E-mailJ.R.Kroep@lumc.nl
    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 AuthorisationNetherlands
    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 Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 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 nameRibociclib
    D.3.2Product code LEE011
    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 INNRIBOCICLIB
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 AuthorisationNetherlands
    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 nameDoxorubicine
    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.3.11 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) Yes
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 AuthorisationNetherlands
    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 nameCyclophosphamide
    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.3.11 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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 AuthorisationNetherlands
    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 nameDocetaxel
    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.3.11 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) Yes
    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: 6
    D.1.2 and D.1.3IMP RoleComparator
    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 AuthorisationNetherlands
    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 namePaclitaxel
    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.3.11 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) Yes
    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
    Mamma carcinoma
    Mammacarcinoom
    E.1.1.1Medical condition in easily understood language
    Breast cancer
    Borstkanker
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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
    Determine if ribociclib plus letrozole gives a ≥100% improvement in complete cell cycle arrest (CCCA; defined as Ki67 IHC <1%) as compared to chemotherapy in the surgical specimen*.

    Bepalen of ribociclib plus letrozol een verbetering van ≥100% geeft in de "complete cell cycle arrest" (CCCA; gedefinieerd als Ki67 IHC <1%) in vergelijking met chemotherapie in het operatie specimen*.
    E.2.2Secondary objectives of the trial
    • Study the correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ®3) and Ki67 mRNA
    • Correlate ER pathway activity at baseline, after two weeks letrozole and at surgery with clinical outcome (collaboration Philips). If sufficient material available additional pathway activities (such as PI3K and others) can be determined
    • Study the difference in pathologic response (pCR and response according to Miller and Payne) between randomized study arms*
    • Determine the change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery
    • Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV*
    • Study the correlation of tumor measurements between standard MRI and palpation at baseline, after AC/before T or 8 weeks of definitive neoadjuvant therapy and pre-surgery
    • Descriptive analysis event free survival (EFS) and overall survival (OS) at 3 and 5 years

    *Objective n.a. to the group with Ki67 <1%
    • De correlatie bestuderen tussen Ki67 IHC handmatig gescoord, IHC automatisch gescoord (Vectra ®3) en Ki67 mRNA
    • De "ER pathway activity" bij start, na twee weken letrozol en bij operatie correleren met de klinische uitkomst (samenwerking Philips). Indien voldoende materiaal beschikbaar kunnen extra "pathway activities"(zoals PI3K e.a.) worden bepaald
    • Het verschil bestuderen in pathologische respons (pCR en respons volgens Miller en Payne) tussen gerandomiseerde studie armen*
    • De verandering in tumor biologie en biomarkers bepalen (ER, PR, HER2, Rb, Ki67) bij start, na twee weken letrozol en bij operatie
    • Toxiciteit volgens de NCI CTCAE v4.03, alle gradaties en gradatie III/IV*
    • De correlatie bestuderen van tumor metingen tussen standaard MRI en palpatie bij start, na AC/voor T of 8 weken definitieve neoadjuvante therapie en voor operatie
    • Beschrijvende analyse "event free survival" en "overall survival" na 3 en 5 jaar

    *Objective n.v.t. op de groep met Ki67 <1%
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Determine the change in ERα DNA binding and gene expression profiling between baseline and after 2 weeks letrozole.
    Bepalen van de verandering in ERα "DNA binding signatures" en "gene expression profiling" bij start en na twee weken letrozol.
    E.3Principal inclusion criteria
    •Postmenopausal women presenting with histological proven (core biopsy material) hormone receptor positive (ER≥50%, PR any), HER2 negative, stage II/ III breast cancer.
    • Measurable disease (breast and/or lymph nodes)
    • WHO 0-2
    • Adequate bone marrow function (within 4 weeks prior to registration): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l
    • Adequate liver function (within 4 weeks prior to registration): bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL
    • Adequate renal function (within 4 weeks prior to registration): the calculated creatinine clearance should be ≥50 ml/min
    • Accessible for treatment and follow-up
    • Written informed consent

    Randomization specific

    • Registration in the NEOLBC trial before 2 weeks biopsy
    • Use of letrozole
    • Outcome central Ki67 determination in two weeks biopsy available.

    • Postmenopauzale vrouwen die zich presenteren met histologisch bewezen (core biopsie materiaal) hormoon receptor positieve (ER≥50%, PR alle), HER2 negatieve, stadium II/III borstkanker.
    • Meetbare ziekte (borst en/of lymfklieren)
    • WHO 0-2
    • Adequate beenmergfunctie (binnen 4 weken voor registratie): leukocyten ≥3.0 x 10^9/l, neutrofielen ≥1.5 x 10^9/l, bloedplaatjes ≥100 x 10^9/l
    • Adequate leverfunctie (binnen 4 weken voor registratie): bilirubine ≤1.5 x bovenste limiet van normaal, ALAT en ASAT ≤2.5 x bovenste limiet van normaal, Alkalische Fosfatase ≤5 x bovenste limiet van normaal
    • Adequate nierfunctie (binnen 4 weken voor registratie): de berekende kreatinine klaring moet ≥50 mL/min zijn
    • Patiënten moeten beschikbaar zijn voor behandeling en follow-up
    • Geschreven informed consent

    Randomisatie specifiek:

    • Registratie in de NEOLBC trial voor 2 weken biopt.
    • Gebruik van letrozol.
    • Uitkomst centrale Ki67 bepaling in twee weken biopt moet beschikbaar zijn.
    E.4Principal exclusion criteria
    • Evidence of distant metastases (M1)
    • Previous invasive breast cancer
    • Prior chemotherapy, radiation therapy or hormonal therapy with the exception of patients who received letrozole ≤ 14 days (+ max. 4 days) prior to registration and who are still on letrozole.
    • Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
    • Peripheral neuropathy > grade 2, whatever the cause
    • Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias or on screening, any of the following cardiac parameters: bradycardia (heart rate <50 at rest) or QTcF ≥450 msec.
    • Known hypersensitivity reaction to any of the components of the treatment (peanuts, soy)
    • Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment,
    prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
    • Currently receiving any of the following substances and cannot be discontinued 7 days prior to randomisation:
    o Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, pomegranate and Seville oranges.
    o That have a known risk to prolong the QT interval or induce Torsades de Pointes.
    o That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
    o Herbal preparations/medications, dietary supplements.
    • Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.
    • Bewijs voor metastasen op afstand (M1)
    • Invasieve borstkanker in de voorgeschiedenis
    • Eerdere behandeling met chemotherapie, radiotherapie of hormonale therapie met de uitzondering van patiënten die letrozol hebben gekregen ≤ 14 dagen (+ max. 4 dagen) voorafgaand aan registratie en die nog steeds letrozol gebruiken.
    • Maligniteit in de afgelopen 5 jaar, met uitzondering van een basaalcelcarcinoom van de huid of pre-invasief carcinoom van de cervix
    • Perifere neuropathie > graad 2, ongeacht de oorzaak
    • Substantiële comorbiditeit zoals infecties (hepatitis B, C en HIV), een recent myocard infarct, klinische tekenen van hartfalen, klinisch significante arrhytmieën of tijdens screening één van de volgende cardiale parameters: bradycardie (hartfrequentie van <50 in rust) of een QTcF ≥450 msec.
    • Bekende overgevoeligheid voor één van de bestanddelen van de behandeling (pinda's, soja).
    • Gebruik van warfarine of een ander coumarinederivaat, voor behandeling, profylaxe of anderszins. Het gebruik van heparine, laag moleculaire heparine of fondaparinux is toegestaan.
    • Gebruik van één van de volgende substanties en kan deze vanaf 7 dagen voor randomisatie niet discontinueren:
    o Bekende sterke inducers of inhibitoren van CYP3A4/5, inclusief grapefruit, grapefruit hybriden, pomelo/pompelmoes, sterfruit, granaatappel en de Sevilla-sinaasappel
    o Die een bekend risico hebben op verlenging van het QT-interval of die Torsades de Pointes induceren
    o Die een smal therapeutisch window hebben en voornamelijk worden gemetaboliseerd door CYP3A4/5
    o Kruidenpreparaten/medicijnen, dieet supplementen
    • Een medische of psychologische conditie die, zoals ingeschat door de onderzoeker, er toe zou leiden dat de patient niet tot het einde van de studie kan participeren of een betekenisvolle informed consent kan geven
    E.5 End points
    E.5.1Primary end point(s)
    Difference in CCCA (defined as Ki67 IHC <1%) between ribociclib plus letrozole and chemotherapy in the surgical specimen*.
    Verschil in CCCA (gedefinieerd als Ki67 IHC <1%) tussen ribociclib plus letrozol en chemotherapie in het operatie specimen*.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At time of operation
    Ten tijde van de operatie
    E.5.2Secondary end point(s)
    • Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.
    • Correlation between ER pathway activity at baseline, after two weeks letrozole and at surgery and clinical outcome. If sufficient sample is available additional pathway activities (such as PI3K and others) can be determined.
    • Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms*.
    • Change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery.
    • Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV*.
    • Correlation of tumor measurements between standard MRI (using RECIST 1.1) and palpation (largest diameter in cm) at baseline, after AC/before T or 8 weeks of definitive neoadjuvant therapy and pre-surgery.
    • Descriptive analysis of event free survival (EFS) and overall survival (OS) at 3 and 5 years.

    * Objective n.a. to the group with a Ki67 of <1%.
    • De correlatie tussen Ki67 IHC handmatig gescoord, IHC automatisch gescoord (Vectra ® 3) en Ki67 mRNA.
    • De correlatie tussen "ER pathway activity" bij start, na twee weken letrozol en bij operatie en de klinische uitkomst. Indien voldoende materiaal beschikbaar is kunnen extra "pathway activities"(zoals PI3K en anderen) worden bepaald.
    • Het verschil in pathologische respons (pCR en respons volgens Miller en Payne) tussen de gerandomiseerde studie armen*.
    • De verandering in tumor biologie en biomarkers (ER, PR, HER2, Rb, Ki67) bij start, na twee weken letrozol en bij operatie.
    • Toxiciteit volgens de NCI CTCAE v4.03, alle gradaties en gradatie III/IV*.
    • De correlatie van tumor metingen tussen standaard MRI (gebruikmakend van RECIST 1.1) en palpatie (grootste diameter in cm) bij start, na AC/voor T of 8 weken definitieve neoadjuvante therapie en voor operatie.
    • Beschrijvende analyse van "event free survival"en "overall survival"na 3 en 5 jaar.

    * Objective n.v.t. op de groep met een Ki67 van <1%.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • At baseline, after two weeks of letrozole and at operation
    • At baseline, after two weeks of letrozole and at operation
    • At operation
    • At baseline, after two weeks of letrozole and at operation
    • From start till end of therapy (every 3 or 4 week, for a total of 24 weeks) + until 30 days after completion of the therapy.
    • At baseline, after AC/before T or 8 weeks of definitive neoadjuvant therapy and before surgery.
    • At 3 and 5 years after registration.
    • Bij start, na twee weken letrozol and bij operatie.
    • Bij start, na twee weken letrozol and bij operatie.
    • Bij operatie.
    • Bij start, na twee weken letrozol and bij operatie.
    • Vanaf begin tot einde therapie (elke 3 of 4 weken, voor een totale duur van ongeveer 24 weken) + tot 30 dagen vanaf het staken van de therapie.
    • Bij start, na AC/voor T of 8 weken definitieve neoadjuvante therapie en voor operatie.
    • Na 3 en 5 jaar.
    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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned20
    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 te core study is defined as the last patient undergoing surgery.
    Het einde van de core studie is gedefinieerd als de laatste patiënt die chirurgie ondergaat.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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.1.1.1In 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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state100
    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)
    None
    Geen
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Dutch Breast Cancer Research Group (BOOG)
    G.4.3.4Network Country Netherlands
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Patient Advocacy Group (PAG)
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-11-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-12
    P. End of Trial
    P.End of Trial StatusOngoing
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