Clinical Trials Register

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

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2017-000676-29

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

NEOLBC study

NEOLBC studie

A.4.1

Sponsor's protocol code number

BOOG-2017-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03283384

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	BOOG Study Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Philips
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Novartis
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leiden University Medical Center
B.5.2	Functional name of contact point	Dr. J.R. Kroep
B.5.3	Address:
B.5.3.1	Street Address	P.O. Box 9600
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2300 RC
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310715263464
B.5.6	E-mail	J.R.Kroep@lumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Letrozole
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ribociclib
D.3.2	Product code	LEE011
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIBOCICLIB
D.3.9.2	Current sponsor code	LEE011
D.3.9.4	EV Substance Code	SUB180246
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Doxorubicine
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cyclophosphamide
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Docetaxel
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Paclitaxel
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Mamma carcinoma

Mammacarcinoom

E.1.1.1

Medical condition in easily understood language

Breast cancer

Borstkanker

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10057654
E.1.2	Term	Breast cancer female
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full 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.
• Determine the effect of ribociclib on the activation, proliferation and differentiation of T cells.
• Determine if there is a (anti)correlation between the delta Ki67 (baseline and 2 weeks letrozole) and estrogen/letrozole levels in the blood.

• Bepalen van de verandering in ERα "DNA binding signatures" en "gene expression profiling" bij start en na twee weken letrozole.
• Bepalen van het effect van ribociclib op de activatie, proliferatie en differentiatie van T cellen.
• Bepalen of er een (anti)correlatie tussen de delta Ki67 (baseline en 2 weken letrozol) en oestrogeen/letrozol spiegels in het bloed.

E.3

Principal 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.4

Principal 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.5.1

Primary 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.5.1.1

Timepoint(s) of evaluation of this end point

At time of operation

Ten tijde van de operatie

E.5.2

Secondary 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.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

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.4.1	Name of Organisation	Dutch Breast Cancer Research Group (BOOG)
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Patient Advocacy Group (PAG)
G.4.3.4	Network Country	Netherlands

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-11-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-01-12

P. End of Trial
P.	End of Trial Status	Ongoing

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