E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with newly, untreated, resectable HR+/HER2- eBCs, suitable for pre-operative therapy with anastrozole |
carcinoma mammario resecabile HR + / HER2- non precedentemente trattati, candidabili alla terapia preoperatoria con anastrozolo |
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E.1.1.1 | Medical condition in easily understood language |
Patients with newly, untreated, resectable HR+/HER2- eBCs, suitable for pre-operative therapy with anastrozole |
carcinoma mammario resecabile HR + / HER2- non precedentemente trattati, candidabili alla terapia preoperatoria con anastrozolo |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the pre-operative activity of ATRA in combination with anastrozole vs. anastrozole alone in operable HR+/HER2- eBCs, via assessment of the proliferative arrest of BC cells (Ki67 level <2.7%). |
- Determinare l¿attivit¿ antitumorale di ATRA, in combinazione con anastrozolo vs anastrozolo da solo in pazienti con carcinoma mammario operabile HR + / HER2- attraverso la misura dell'arresto proliferativo secondo il livello di Ki67 <2,7%. |
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E.2.2 | Secondary objectives of the trial |
1. To assess the activity of ATRA according to the % of Ki67 reduction, measured before and after treatment. 2. To assess the activity of ATRA in terms of tumor size reduction and response rate, according to the RECIST criteria, after 4 weeks of therapy. 3. To validate the predictive power of ATRA-21, a gene-expression model associated with ATRA activity. 4. To assess the safety and tolerability of ATRA administrated daily p.o. for 4 weeks in combination with anastrozole. |
1. Valutare l'attivit¿ di ATRA in base alla riduzione % di Ki67, misurata prima e dopo il trattamento 2. Valutare l'efficacia di ATRA in termini di riduzione della dimensione del tumore dopo 4 settimane di terapia, secondo i criteri RECIST 3. Valutare i potenziali biomarcatori predittivi di sensibilit¿ ad ATRA (i.e.ATRA21) 4. Valutare la sicurezza e la tollerabilit¿ di ATRA somministrato quotidianamente per via orale per 4 settimane in combinazione con anastrozolo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed, informed consent 2. Histologically confirmed non-metastatic operable primary invasive HR-positive breast cancer subjected to diagnostic core biopsy 3. Menopausal status 4. HR-positive/HER2-negative eBC defined as - ER>1% on immunohistochemistry (IHC) staining - HER2 score equal to 0, 1+, 2+ (if FISH neg) on IHC staining 5. Available paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for Ki67 determination (IHC) 6. Adequate bone marrow, hepatic and renal function including the following a. Hb = 9.0 g/dL, absolute neutrophil count = 1.5 x 109/L, platelets =100 x 109/L b. Total bilirubin = 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome c. AST (SGOT), ALT (SGPT) = 2.5 x upper normal limit (or 5x UNL in the presence of liver metastases) d. Creatinine = 1.5 x upper normal limit 7. Age = 18 years 8. Performance status (PS) = 1 (ECOG scale). |
1. Consenso informato scritto 2. Diagnosi di Carcinoma mammario infiltrante HR positivo, non metastatico, confermato istologicamente 3. Stato menopausale 4. Positività immunoistochimica per HR / HER2 definita come: ER> 1%, HER2 uguale a 0, 1+, 2+ (se FISH neg) 5. Disponibilità di tessuto tumorale della biopsia incluso in paraffina (FFPE) per la determinazione immunoistochimica di Ki67 6. Funzionalità adeguata funzionalità epatica, renale ed emopoietica: a. Hb = 9,0 g / dL, conta assoluta dei neutrofili = 1,5 x 109 / L, piastrine =100 x 109 / L b. Bilirubina totale = 1,5 x UNL, esclusi i casi in cui la bilirubina elevata può essere attribuita alla sindrome di Gilberts c. AST (SGOT), ALT (SGPT) = 2,5 x UNL (o 5x UNL in presenza di metastasi epatiche) d. Creatinina = 1,5 x UNL 7. Età = 18 anni 8. Pazienti con performance status (Eastern Cooperative Oncology Group) = 1 . |
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E.4 | Principal exclusion criteria |
1. Presence of metastatic disease 2. Pre-menopausal status 3. Previous investigational treatment for any condition within 4 weeks of randomization date 4. Treatment including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry 5. Co-existing active infection or serious concurrent illness 6. Any medical or other condition that in the Investigator’s opinion renders the patient unsuitable for this study due to unacceptable risk 7. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies 8. Gastrointestinal disorders that may interfere with absorption of the study drug. |
1. Presenza di malattia metastatica 2. Stato pre-menopausale 3. Precedente trattamento con farmaci sperimentali entro 4 settimane dalla data di randomizzazione 4. Trattamento comprendente radioterapia, chemioterapia, bioterapia e / o terapia ormonale per il carcinoma mammario attuale prima dell'ingresso nello studio 5. Infezione attiva coesistente o malattia concomitante grave 6. Qualsiasi condizione medica o di altra natura che secondo l'opinione dell'investigatore rende il paziente inadatto alla partecipazione allo studio a causa di un rischio inaccettabile 7. Disturbi psichiatrici o alterazione dello stato mentale che impediscono la comprensione del consenso informato e / o il completamento delle valutazioni richieste da protocollo 8. Disturbi gastrointestinali che possono interferire con l'assorbimento del farmaco in studio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
to investigate the primary objective, we will compare the proportion of responder patients in the 2 arm (Aa vs. a) according to the Ki67 assessment, measured at baseline and after treatment. |
per studiare l'obiettivo primario, confronteremo la proporzione di pazienti responder nel braccio Aa vs. a, secondo la valutazione del Ki67, misurata al basale e dopo il trattamento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary study end-point will be evaluated at the time of surgery after 28 days of treatment. |
L'endpoint primario dello studio sarà valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento. |
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E.5.2 | Secondary end point(s) |
we will compare the % change in the Ki67 level from baseline in the two treatment groups.; we will determine clinical efficacy (overall response rate, ORR) in terms of tumor size reduction (RECIST criteria) and in terms of pathologic complete responses at the time of surgical resection.; Further exploratory analysis for the identification of correlative biomarkers: we will calculate associations between the Ki67 results and the PAM50 proliferative signature. Moreover we will evaluate the association between Ki67 level and ATRA-21 to test the predictive power of the gene-expression model. Moreover we will determine the ATRA-21 signature, which predicts sensitivity of BC cell lines with great accuracy, and will be validated in the current clinical trial. ATRA-21 consists of 21 genes and the gene-expression signature can be determined from the RNA-sequencing data obtained in basal conditions. Correlations between ATRA-21 predictions and the response of patients to ATRA+anastrozole will be evaluated.; Patients will be monitored for adverse events (AEs) bi-weekly using the definitions and criteria for grading provided in the Common Terminology Criteria for adverse Events (CTCAE) 4.03. |
confronteremo la variazione% nel livello di Ki67 rispetto al basale nei due gruppi di trattamento.; b) determineremo l'efficacia clinica (tasso di risposta globale, ORR) in termini di riduzione della dimensione del tumore (criteri RECIST) e in termini di risposte patologiche complete al momento della resezione chirurgica.; c) Ulteriori analisi esplorative per l'identificazione di biomarcatori correlati: calcoleremo le associazioni tra i risultati del Ki67 e la firma proliferativa del PAM50. Inoltre valuteremo l'associazione tra il livello di Ki67 e l'ATRA-21 per testare il potere predittivo del modello di espressione genica, previamente definito. Inoltre determineremo la capacit¿ della firma genica definita ATRA-21 nel predire la sensibilit¿ al trattamento. ATRA-21 consiste di 21 geni e la firma di espressione genica potr¿ essere determinata per sequenziamento dell'RNA tumorale ottenuto in condizioni basali. Verranno valutate le correlazioni tra l¿espressione di ATRA-21 e la risposta dei pazienti al trattamento; I pazienti saranno monitorati per eventi avversi (AE) bisettimanale utilizzando le definizioni e i criteri per la classificazione forniti nei Common Terminology Criteria for adverse Events (CTCAE) 4.03. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary study end-point will be evaluated at the time of surgery after 28 days of treatment.; The secondary study end-point will be evaluated at the time of surgery after 28 days of treatment.; The secondary study end-point will be evaluated at the time of surgery after 28 days of treatment.; 30 days after the last dose of study treatment. |
L'endpoint secondario dello studio sar¿ valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.; L'endpoint secondario dello studio sar¿ valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.; L'endpoint secondario dello studio sar¿ valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.; 30 giorni dopo l'utlima dose del farmaco in studio. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |