| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple Negative Breast Cancer |
| Carcinoma della mammella triplo negativo |
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| E.1.1.1 | Medical condition in easily understood language |
| Triple Negative Breast Cancer |
| Tumore al seno triplo negativo |
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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 | 10075566 |
| E.1.2 | Term | Triple negative 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 |
1. To address in patients with TNBC the anti-tumor activity of pre-operative standard chemotherapy associated or not with zoledronate (zol) and atorvastatin measured through its effect on YAP and TAZ IHC expressions, which are considered co-primary objectives
2. Clinical objective: to assess the anti-tumor activity of the combination of neoadjuvant standard chemotherapy associated with zoledronate (zol) and atorvastatin, measured by the proportion of pCR obtained after neoadjuvant treatment in patients with TNBC.
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1. Obiettivo proof of concept: valutare in pazienti con TNBC l¿attivit¿ antitumorale della chemioterapia neoadiuvante standard in associazione a zoledronato e atorvastatina verso la sola chemioterapia, analizzata attraverso l¿effetto del trattamento sull¿espressione sia di YAP sia di TAZ (tramite analisi immunoistochimica), considerati obiettivi co-primari.
2. Obiettivo clinico: valutare l¿attivit¿ antitumorale della chemioterapia neoadiuvante standard in associazione a zoledronato e atorvastatina in termini di percentuale di risposte patologiche complete (pCR).
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the anti-tumor activity of pre-operative standard chemotherapy associated or not with zoledronate (zol) and atorvastatin according to high/low p53 levels, measured through its effect on both YAP and TAZ IHC expressions and the proportion of pCR
2. To address the efficacy of neoadjuvant chemotherapy associated or not with zoledronate/atorvastatin combo in terms of disease free survival (DFS) and overall survival (OS)
3. To study the safety profile of neoadjuvant chemotherapy associated or not with zoledronate/atorvastatin combo, evaluated by the NCI CTCAE scale version 4.03 and by the occurrence of serious adverse events
4. To investigate the treatment modulation (up/down regulation) of YAP and TAZ gene expression (RNA-Seq) in tumor tissues collected at the time of core-biopsy and definitive surgery
5. To address the modulation of Ki67expression by IHC in the FFPE diagnostic core biopsy and in tumor tissue collected at surgery. |
1. Valutare l¿attivit¿ antitumorale della chemioterapia preoperatoria standard in associazione a zoledronato (zol) e atorvastatina rispetto al livello (alto/basso) di p53, analizzando l¿effetto del trattamento sull¿espressione di YAP e TAZ tramite IHC e la percentuale di pCR.
2. Valutare l¿efficacia della chemioterapia neoadiuvante in associazione o meno a zoledronato e atorvastatina in termini di DFS e OS.
3. Studiare il profilo di sicurezza dei trattamenti in studio.
4. Verificare attraverso RNA-Seq la modulazione (aumento o diminuzione) dell¿espressione genica di YAP e TAZ nel tessuto tumorale indotta dal trattamento, analizzando l¿espressione dei suddetti geni nel campione di tumore raccolto alla diagnosi e alla chirurgia.
5. Valutare attraverso l¿analisi immunoistochimica la modulazione del livello di espressione di Ki67 indotta dal trattamento, analizzando la espressione di Ki67 nel campione di tumore prelevato alla diagnosi e nel tessuto tumorale raccolto alla chirurgia. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of non-metastatic operable TNBC subjected to diagnostic core biopsy
2. TNBC defined as HER2/ER/PgR negative receptors
3. Female, aged = 18 years
4. ECOG (Eastern Cooperative Oncology Group) performance status = 1
5. Clinical indication for a neoadjuvant approach according to the investigator‘s judgment. The standard chemotherapy will consist of a complete pre-operative treatment with anthracyclines and taxanes (in sequence or combination), including platinum derivatives and dose-dense schedules, according to the best physician choice (BPC)
6. Availability of paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for IHC
7. Patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to study entry. They must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment
8. Written informed consent signed prior to enrolment according to ICH/GCP.
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1. Conferma istologica di TNBC operabile, non metastatico sottoposto a biopsia diagnostica
2. TNBC definito come HER2/ER/PgR negativo
3. Donne di età uguale o superiore a 18 anni
4. ECOG (Eastern Cooperative Oncology Group) performance status = 1
5. Indicazione al trattamento neoadiuvante secondo la decisione del clinico. La chemioterapia standard prevederà il trattamento pre-operatorio con atracicline e taxani (in sequenza o combinazione), inclusi i derivati del platino e la schedula dose-dense, secondo la scelta del clinico
6. Disponibilità del pezzo tumorale incluso in paraffina (FFPE) prelevato alla biopsia diagnostica per le analisi immunoistochimiche
7. Per le donne in età fertile: test di gravidanza negativo nei 7 giorni precedenti l’inclusione nello studio e l’utilizzo di un adeguato metodo contraccettivo durante tutto il periodo di trattamento e per un minimo di 3 mesi dopo l’ultima somministrazione del trattamento in studio
8. Consenso informato scritto, firmato prima di intraprendere qualsiasi procedura correlata allo studio, in accordo con ICH/GCP.
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| E.4 | Principal exclusion criteria |
1. Presence of metastatic disease
2. Previous investigational treatment for any condition within four weeks prior to study registration
3. Treatment with bisphosphonates, denosumab or other drug that, in the investigator’s judgment, affects bone metabolism
4. Treatment with statins or other drugs that, in the investigator’s judgment, potentially affect the mevalonate pathway
5. Any previous treatment for the currently diagnosed breast cancer, including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy
6. Inadequate bone marrow, hepatic or 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 ULN, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
c. AST (SGOT), ALT (SGPT) > 2.5 x ULN
d. Creatinine > 1.2 x ULN, calcium < 8.6 mg/dL
7. Co-existing active infection or concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study
8. Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
9. Co-existing dental diseases that form a contraindication to the use of zol
10. Any medical or other condition that in the Investigator’s opinion renders the patient unsuitable for this study due to unacceptable risk
11. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures
12. Known hypersensitivity to the active substance, to other bisphosphonates or to any excipients of zoledronate
13. Known hypersensitivity to the active substance or to any excipients of atorvastatin. Conditions of rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption
14. Anticipation of need for major surgical procedure during the course of the trial
15. Pregnant or breast feeding women.
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1. Presenza di malattia metastatica
2. Precedente trattamento sperimentale per qualsiasi condizione medica nelle quattro settimane precedenti l’arruolamento nello studio
3. Trattamento con bifosfonati, denosumab o altri farmaci che, a giudizio del medico, vanno ad agire sul metabolismo osseo
4. Trattamento con statine o altri farmaci che, a giudizio del medico, possono agire sulla via del mevalonato
5. Qualsiasi precedente trattamento per il carcinoma della mammella attualmente diagnosticato, inclusa la radioterapia, la chemioterapia, la terapia con farmaci biologici e/o la terapia ormonale
6. Inadeguata funzionalità renale, epatica e midollare:
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 ULN, esclusi i casi di Sindrome di Gilberts
c. AST (SGOT), ALT (SGPT) > 2.5 x ULN
d. Creatinina > 1.2 x ULN, calcio < 8.6 mg/dL
7. Infezioni attive o malattie concomitanti che, a giudizio dello sperimentatore, rendano controindicato l'inserimento della paziente nello studio
8. Malattia epatica in fase attiva o con inspiegabili persistenti aumenti delle transaminasi, oltre 3 volte il limite normale superiore
9. Malattie dentali concomitanti che creino una controindicazione all'uso di zoledronato
10. Qualsiasi condizione medica o di altro tipo che, a giudizio dello sperimentatore, renda la paziente inadatta per questo studio
11. Disordini psichiatrici o stato mentale alterato che precludano la comprensione del consenso informato e/o il completamento delle valutazioni e delle procedure previste dallo studio
12. Ipersensibilità nota al principio attivo, ad altri bisfosfonati o ad uno qualsiasi degli eccipienti dello zoledronato
13. Nota ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti della atorvastatina. Rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento di glucosio-galattosio
14. Necessità della paziente di sottoporsi a importanti interventi chirurgici durante lo studio
15. Donne in gravidanza o in allattamento.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The proof of concept co-primary endpoints are the relative reductions of YAP and TAZ IHC expression at surgery with respect to core-biopsy analysis;
- the clinical endpoint is the proportion of responder patients defined as those obtaining a pCR, defined as ypT0ypN0 or as the absence of any residual tumor burden at surgery.
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| Gli endpoint primari di attività dello studio sono:proof of concept endpoint: riduzione relativa dell’espressione di YAP e TAZ determinata attraverso IHC nel campione di tessuto tumorale analizzato alla chirurgia rispetto al contenuto di YAP e TAZ nel campione di tumore analizzato alla diagnosi. - endpoint clinico: percentuale di pazienti rispondenti. Vengono definite rispondenti quelle pazienti in cui si è ottenuta una pCR, definita come ypT0ypN0 o assenza di tumore residuo alla chirurgia. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary Endpoints will be evalueted at surgery, after 6 months of neoadjuvant treatment. |
| Gli endpoint primari verranno valutati alla chirurgia, dopo 6 mesi di trattamento neodiuvante. |
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| E.5.2 | Secondary end point(s) |
| Relative reductions of YAP and TAZ IHC-expression at surgery with respect to core-biopsy analysis according to high/low p53 levels. A high level of p53 is defined by IHC expression =30%, while a low level by IHC expression <30%.; Proportion of responder patients according to high/low p53 levels; DFS, defined as the time from the date of treatment start to the first of either recurrence or relapse, second cancer, or death.; Overall survival (OS), defined as the time from the date of treatment start to the date of death from any cause. ; The study treatment safety profile will be evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, and by the incidence of serious adverse events (SAEs), expected and unexpected.; Proportions of patients with down regulation of YAP and TAZ gene expression by RNA-Seq in tumor tissue samples collected at definitive surgery with respect to tumor tissue collected at the time of core-biopsy for responder and non-responders patients. ; Relative reduction of Ki67 IHC expression in tumor tissue sample collected at definitive surgery with respect to tumor tissue collected at the time of diagnostic core-biopsy for responder and non-responders patients. |
| Riduzione relativa dell¿espressione di YAP e TAZ (attraverso IHC) alla chirurgia rispetto alla biopsia alla diagnosi in base al livello alto/basso di p53. Il livello di p53 tramite analisi IHC ¿ definito alto quando il contenuto di p53 nel campione tumorale ¿ =30%, mentre ¿ definito basso quando il contenuto di p53<30%.; Percentuale di pazienti rispondenti in base al livello di p53 (alto/basso).; DFS, definita come il tempo intercorso dalla data di inizio del trattamento alla prima progressione/ ripresa di malattia, tumore secondario o morte.; Sopravvivenza globale (OS), definita come il tempo intercorso dalla data di inizio del trattamento alla data di decesso per ogni causa. ; Il profilo di sicurezza del trattamento in studio sar¿ valutato in accordo all¿NCI-CTCAE versione 4.03 e verr¿ valutata l¿incidenza dei SAE, attesi e inattesi. ; Percentuale di pazienti con diminuzione dell¿espressione genica di YAP e TAZ (analizzata attraverso RNA-Seq) nel tessuto tumorale raccolto alla chirurgia rispetto al campione di tumore della biopsia diagnostica.; Riduzione relativa dell¿espressione di Ki67 (attraverso IHC) nei campioni di tessuto tumorale raccolti alla chirurgia rispetto a quelli raccolti alla diagnosi. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| This endpoint will be evaluated at surgery; This endpoint will be evaluated at surgery; Date of first recurrence or relapse, second cancer, or death. Subjects alive and without tumor at the end of the study will be censored at the last disease assessment date.; Date of death from any cause. Patients not reported as having died at the end of the study will be censored at the date they were last known to be alive.; The study treatment safety profile will be evaluated during the study period.; This endpoint will be evaluated at surgery.; This endpoint will be evaluated at surgery. |
| Questo endpoint verr¿ valutato alla chirurgia; Questo endpoint verr¿ valutato alla chirurgia; Data di prima progressione/ ripresa di malattia, tumore secondario o morte. I soggetti vivi e senza malattia alla fine dello studio saranno censorizzati alla data dell¿ultima valutazione della malattia.; Data di decesso per ogni causa. Le pazienti che non risultassero decedute alla fine dello studio verranno censorizzate all¿ultima data nota in cui risultavano essere vive.; Il profilo di sicurezza verr¿ valutato per tutta la durata dello studio.; Questo endpoint verr¿ valutato alla chirurgia.; Questo endpoint verr¿ valutato alla chirurgia. |
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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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Due fasi: la prima randomizzata, la seconda prevede la registrazione nel braccio sperimentale |
| Two phases: first one randomized, in the second one pts will be registered in the exsperimental arm |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Chemioterapia neoadiuvante standard |
| Neoadjuvant stardard chemotherapy |
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| 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
| No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | 3 |
| 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 | 3 |
| 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 |
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