E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced, inflammatory or early stage HER2 positive breast cancer. |
Carcinoma della mammella HER2 positivo localmente avanzato, infiammatorio o in stadio precoce. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006200 |
E.1.2 | Term | Breast cancer stage II |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006201 |
E.1.2 | Term | Breast cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021974 |
E.1.2 | Term | Inflammatory 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 make a preliminary assessment of the efficacy of neoadjuvant treatment of trastuzumab and docetaxel as compared to trastuzumab, pertuzumab and docetaxel as compared to trastuzumab and pertuzumab, in patients with T2-4d HER2 positive breast cancer, based on complete pathological response rate. |
Effettuare una valutazione preliminare dell`efficacia, sulla base del tasso di risposta patologica completa, del trattamento neoadiuvante con trastuzumab e docetaxel a confronto con trastuzumab, pertuzumab e docetaxel e a confronto con trastuzumab e pertuzumab e del trattamento neoadiuvante con pertuzumab e docetaxel a confronto con trastuzumab, pertuzumab e docetaxel, in pazienti affette da carcinoma della mammella HER2 positivo in stadio T2-4d. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety profiles of each treatment regimen, including pre-operative (neoadjuvant) and post-operative (adjuvant) treatment. To determine the time to clinical response, time-to-response, disease free survival and progression free survival for each treatment arm. To evaluate the biomarkers that may be associated with primary and secondary efficacy endpoints in accordance with each treatment arm. To evaluate the rate of breast conservative surgery for all patients with T2-3 tumors for whom mastectomy was planned at diagnosis. |
Valutare il profilo di sicurezza di ciascun regime di trattamento,compresi quelli pre-operatorio (neoadiuvante) e post-operatorio (adiuvante).Determinare il tempo alla risposta clinica (clinical response),il tempo alla risposta (time to response),la sopravvivenza libera da malattia (disease free survival) e la sopravvivenza libera da progressione (progression free survival) per ciascun braccio di trattamento.Valutare i biomarcatori che potrebbero essere associati agli endpoints di efficacia primari e secondari per ciascun braccio di trattamento.Valutare il tasso di chirurgia conservativa della mammella per tutte le pazienti affette da neoplasia in stadio T2-3 per le quali alla diagnosi era stata pianificata la mastectomia. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female patients ≥18 years with locally advanced, inflammatory or early stage, unilateral and histologically confirmed invasive breast cancer . 2. Primary tumor > 2cm in diameter. 3. HER2 positive confirmed by a central laboratory. Tumors must be HER2+++ by IHC or FISH/CISH + (FISH/CISH mandatory for HER2 ++ tumors). 4. Availability of FFPE tissue for central confirmation of HER2 eligibility (FFPE tumor tissue will subsequently be used for assessing status of biomarkers). 5. Age ≥ 18. 6. Baseline LVEF of ≥ 55% (measured by echocardiogram or MUGA). 7. Performance status ECOG Scale ≤ 1. 8. At least 4 weeks since major unrelated surgery, with full recovery. 9. A negative pregnancy test must be available for pre-menopausal women and for women less than 2 years after the onset of menopause. 10. Signed informed consent. |
1.Donne di eta` ≥18 anni con carcinoma della mammella localmente avanzato, infiammatorio o in stadio precoce, unilaterale e invasivo confermato istologicamente. 2.Neoplasia primaria > 2 cm di diametro. 3.Positivita` HER2 confermata da un laboratorio centrale. Il tumore deve essere HER2+++ in base ad esame immuno-istochimico (IHC) o positivo al test di ibridazione in situ tramite fluorescenza (FISH) o ibridazione cromogenica in situ (CISH) (FISH/CISH obbligatorio per tumori HER2++). 4.Disponibilita` di tessuto fissato in formalina e incluso in paraffina (FFPE) per la conferma centralizzata del criterio di idoneita` HER2 (il tessuto neoplastico FFPE sara` utilizzato successivamente per valutare lo stato dei biomarcatori). 5.Eta` > 18 anni. 6.Frazione di eiezione ventricolare sinistra (LVEF) basale > 55% (misurata con ecocardiogramma o MUGA). 7.Performance status ECOG < 1. 8.Almeno 4 settimane dall`ultimo intervento chirurgico importante non correlato alla patologia, con recupero completo. 9.Per le donne in premenopausa e le donne a meno di 2 anni dall`insorgenza della menopausa deve essere disponibile un test di gravidanza negativo. 10.Consenso informato firmato. |
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E.4 | Principal exclusion criteria |
1. Metastatic disease (Stage IV) or bilateral breast cancer. 2. Previous anticancer therapy or radiotherapy for any malignancy. 3. Other malignancy, except for carcinoma in situ of the cervix or basal cell carcinoma. 4. Inadequate bone marrow function (e.g. Absolute Neutrophil Count (ANC) <1.5 x 1,000,000,000/L, Platelet count < 100 x 1,000,000,000/L and Hb < 9 g/dL ). 5. Impaired liver function: (e.g. serum [total] bilirubin > 1.25 x ULN (with the exception of Gilbert s syndrome), AST, ALT > 1.25 x ULN, albumin < 25 g/L 6. Inadequate renal function, serum creatinine >1.5 x ULN. 7. Uncontrolled hypertension (systolic > 150 and/or diastolic > 100), unstable angina, CHF of any NYHA classification, serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial. infarction within 6 months of enrollment, or LVEF < 55%. 8. Dyspnea at rest or other diseases which require continuous oxygen therapy. 9. Severe uncontrolled systemic disease (e.g. hypertension, clinically significant cardiovascular, pulmonary, metabolic, wound-healing, ulcer, or bone fracture). 10. Subjects with insulin-dependent diabetes. 11. Pregnant and/or lactating women. 12. Subjects with reproductive potential not willing to use highly effective nonhormonal method of contraception or two effective forms of non-hormonal contraception. Contraception use must continue for the duration of study treatment and for at least 6 months post discontinuation of study treatment. For details please see Section 7.2.4. 13. Received any investigational treatment within 4 weeks of study start. 14. Subjects with known infection with HIV, HBV, HCV. 15. Known hypersensitivity to any of the study drugs or excipients. 16. Subjects assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol. |
1. Tumore metastatico (stadio IV) o carcinoma della mammella bilaterale. 2. Precedente terapia antineoplastica o radioterapia per qualsiasi neoplasia maligna. 3. Altra neoplasia maligna, ad eccezione del carcinoma in situ della cervice uterina o del carcinoma a cellule basali. 4. Funzionalita` del midollo osseo non adeguata [es. conta assoluta dei neutrofili (ANC) < 1,5 x 109/l, conta piastrinica < 100 x 109/l e Hb < 9 g/dl]. 5. Compromissione della funzionalita` epatica: [es. bilirubina sierica (totale) > 1,25 volte il limite superiore di normalita` (ULN) (ad eccezione dei casi di sindrome di Gilbert), AST, ALT > 1,25 volte il limite superiore di normalita` (ULN), albumina < 25 g/l]. 6. Funzionalita` renale non adeguata, creatinina sierica >1,5 volte il limite superiore di normalita` (ULN). 7. Ipertensione non controllata (sistolica > 150 e/o diastolica > 100), angina instabile, insufficienza cardiaca congestizia (CHF) di qualsiasi tipo rispetto alla classificazione NYHA, aritmia cardiaca seria che richieda un trattamento (ad eccezione di fibrillazione atriale, tachicardia parossistica sopraventricolare), anamnesi di infarto del miocardio nei 6 mesi precedenti il reclutamento, o LVEF < 55%. 8. Dispnea a riposo che richieda ossigenoterapia continuativa. 9. Patologia sistemica grave non controllata (es. ipertensione, disturbo cardiovascolare, polmonare, metabolico, cicatrizzazione, ulcera o frattura ossea clinicamente significativo). 10. Soggetti con diabete insulino-dipendente. 11. Donne in gravidanza e/o in allattamento al seno. 12. Soggetti in eta` fertile non disposti a utilizzare metodi contraccettivi non-ormonali altamente efficaci o due metodi di contraccezione non ormonali efficaci. L¿uso di contraccettivi dovra` protrarsi per tutta la durata dello studio e per almeno 6 mesi dopo l¿ultima dose di trattamento previsto dallo studio. 13. Somministrazione di qualsiasi trattamento sperimentale nelle 4 settimane prima dell`inizio dello studio. 14. Soggetti con infezioni conclamate da HIV, HBV, HCV. 15. Ipersensibilita` nota a uno qualsiasi dei farmaci dello studio o degli eccipienti. 16. Soggetti che a giudizio dello sperimentatore non siano in grado o disposti a conformarsi ai requisiti del protocollo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pathological CR in the active arms |
Risposta patologica completa nei bracci attivi |
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 4 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 | No |
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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Il termine dello studio sara` a 5 anni dalla randomizzazione dell`ultimo paziente o progressione della malattia determinata in tutti i pazienti, a seconda di quale degli eventi si verifichi per primo. |
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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 | 7 |
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 | 7 |
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 |