| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| breast cancer patients |
| pazienti con carcinoma mammario |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with breast cancer |
| pazienti affette da tumore mammario |
|
| 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 | 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 1. The primary objective of the MINDACT trial is to demonstrate the superiority of the molecular profiling approach over the usual clinical assessment in assigning adequate risk categories (and the need to receive adjuvant chemotherapy or not) to breast cancer patients with 0 to 3 positive lymph nodes. 2. The trial will also aim to compare a docetaxel-capecitabine regimen possibly associated with increased efficacy and reduced long-term toxicities to existing commonly used anthracycline-based chemotherapy regimens (anthracyclines followed by docetaxel for node positive). 3. The last primary objective will be to determine the best endocrine treatment strategy i.e. single agent up-front, aromatase inhibitor (AI) (letrozole) for seven years compared to the sequential endocrine strategy of 2 years of tamoxifen followed by 5 years of letrozole. |
| 1. The primary objective of the MINDACT trial is to demonstrate the superiority of the molecular profiling approach over the usual clinical assessment in assigning adequate risk categories (and the need to receive adjuvant chemotherapy or not) to breast cancer patients with 0 to 3 positive lymph nodes. 2. The trial will also aim to compare a docetaxel-capecitabine regimen possibly associated with increased efficacy and reduced long-term toxicities to existing commonly used anthracycline-based chemotherapy regimens (anthracyclines followed by docetaxel for node positive). 3. The last primary objective will be to determine the best endocrine treatment strategy i.e. single agent up-front, aromatase inhibitor (AI) (letrozole) for seven years compared to the sequential endocrine strategy of 2 years of tamoxifen followed by 5 years of letrozole. |
|
| E.2.2 | Secondary objectives of the trial |
| Estimation of disease free survival, distant metastasis free survival, overall survival of chemotherapy in the groups where the prognostic methods are discordant. Calculation of overall estimates of efficacy for each treatment strategy according to the prognostic methods. Estimation of the % of patients receiving chemotherapy per each prognostic method. To identify and/or validate predictive gene expression profiles of clinical response/resistance to anthracycline and docetaxel`ˆ'capecitabine chemotherapy, and novel gene expression signatures predicting clinical response to sequential tamoxifen`ˆ'AI versus AI alone. To compare the OS distributions associated with the 2 chemotherapy arms. To determine and compare early and late toxicities associated with each arm. To evaluate adjuvant endocrine treatment success or failure in the group of postmenopausal patients with endocrine responsive disease. To compare the safety profile of the two endocrine therapy regimens |
| Estimation of disease free survival,distant metastasis free survival,overall survival of chemotherapy in the groups where the prognostic methods are discordant Calculation of overall estimates of efficacy for each treatment strategy according to the prognostic methods Estimation of the % of patients receiving chemotherapy per each prognostic method To identify and/or validate predictive gene expression profiles of clinical response/resistance to anthracycline and docetaxel-capecitabine chemotherapy,and novel gene expression signatures predicting clinical response to sequential tamoxifen-AI versus AI alone To compare the OS distributions associated with the chemotherapy regimens To determine and compare early and late toxicities associated with each regimen To evaluate adjuvant endocrine treatment success or failure in the group of postmenopausal patients with endocrine responsive disease To compare the safety profile of the two endocrine therapy regimens |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| women with histologically proven operable invasive breast cancer, with 0 to 3 positive lymph nodes and no distant metastases. acceptable treatment options are: ¨ breast conserving surgery or mastectomy with either a sentinel node procedure or full axillary clearance. ¨ radiotherapy is mandatory in the case of breast conserving surgery and will be administered according to local institutional policy after mastectomy. ¨ patients with unresectable positive deep margins who will receive adjuvant radiotherapy are eligible provided that all other margins are negative. ¨ with a clinical tumor classification of T1, T2 or operable T3. ¨ the breast tumor must be unilateral. Multi focal tumors are allowed provided that they have identical histology.DCIS or LCIS are allowed if invasive cancer is present. ¨ a frozen tumor sample (not fixed in formalin) must be available for inclusion. The tumor sample must be taken from the excised primary tumor (a core punch biopsy). ¨ patients should be aged ³ 18 years at randomization. ¨ have a WHO performance status of 0 or 1. ¨ have adequate bone marrow reserves (neutrophil count >1.5 x109 /l and platelet count >100 x109/l), adequate renal function (serum creatinine ≤ 1.5 x upper limit of normal) and hepatic function (ALAT, ASAT ≤ 2.5 x upper limit of normal, alkaline phosphatase ≤ 2.5 x upper limit of normal and total bilirubin ≤ 2.0 x upper limit of normal). |
| • Donne con carcinoma della mammella confermato istologicamente, operabile, con 0-3 linfonodi positivi e assenza di metastasi a distanza. Opzioni di trattamento accettabili: o Chirurgia conservativa della mammella o mastectomia radicale con procedura per il linfonodo sentinella o linfadenectomia totale ascellare. o La radioterapia e' obbligatoria nel caso di chirurgia conservativa della mammella. Nel caso di mastectomia dovra' essere somministrata in accordo con le linee guida istituzionali locali. o Le pazienti con margini profondi positivi non resecabili che ricevono radioterapia sono eleggibili solo se gli altri margini sono negativi. • Classificazione del tumore T1, T2 o T3 operabile. • Il tumore della mammella deve essere unilaterale. Tumori multifocali sono accettati, ammesso che abbiano stesso tipo istologico. Sono comunque permessi tumori del tipo DCIS o LCIS in presenza di tumore invasivo. • Deve essere disponibile per l’inclusione un campione di tumore congelato (non fissato in formalina) . Il campione deve essere escisso dal tumore primario (biopsia del tipo “core punch”). • Eta': superiore o uguale a 18 anni alla randomizzazione. • Performance Status WHO di 0 o 1. • Per ricevere la chemioterapia, le pazienti devono avere un`adeguata riserva midollare (conta neutrofili >1.5x109/l e conta delle piastrine >100x109/l), adeguata funzionalita' renale (creatinina sierica ≤1.5xUNL), adeguata funzionalita' epatica (ALAT e ASAT≤2.5x UNL, fosfatasi alcalina ≤2.5 UNL, bilirubina totale ≤ 2x UNL) |
|
| E.4 | Principal exclusion criteria |
| have NO serious cardiac illness or medical condition including but not confined to: a history of documented congestive heart failure (CHF), high-risk uncontrolled arrhythmias, angina pectoris requiring antianginal medication, clinically significant valvular heart disease, evidence of transmural infarction on ECG, poorly controlled hypertension (e.g. systolic > 180 mm Hg or diastolic > 100 mm Hg), symptomatic coronary artery disease or a myocardial infarction within the last 12 months or other risk factors that contra-indicate the use of anthracycline-based chemotherapy. ¨ NOT have serious uncontrolled intercurrent infections, or other serious uncontrolled concomitant disease. ¨ NOT have previous or concurrent cancer, possible exceptions are: adequately treated carcinoma in situ of the cervix, non-melanoma skin cancer, lobular or ductal carcinoma in situ of the breast and any invasive cancer (other than breast cancer) in complete remission for ≥ 5 years. ¨ NOT have received (neo) adjuvant chemotherapy, (neo) adjuvant endocrine therapy or radiotherapy for the primary breast cancer considered for this trial. ¨ NOT have participated in any investigational drug study within the 4 weeks preceding the start of treatment. ¨ NOT be pregnant or breast-feeding at the time of diagnosis or randomization. A woman of childbearing potential must have a negative pregnancy test. If post-menopausal, the woman must have been amenorrheic for at lest 12 months to be considered of non-childbearing potential while taking study medications patients should take adequate birth control measures which result in low failure rates (i.e. less then 1% per year) when used consistently and correctly such as implants, some IUDs, condoms, sexual abstinence or vasectomised partner (Note 3 of the guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals CPMP/ICH/286/95). ¨ NOT have any psychological, familial, sociological, geographical or serious uncontrolled medical (e.g. a history of uncontrolled seizures, central nervous system disorders, or psychiatric disability) condition judged by the investigator to be clinically significant which could potentially preclude informed consent or interfere with compliance for oral drug intake or with the study protocol and follow-up schedule. These conditions should be discussed with the patient before enrollment in the trial. |
| • Le pazienti non devono avere infezioni ricorrenti non controllate o altre malattie concomitanti non controllate. • Assenza di altri tumori precedenti o concomitanti ad eccezione di: carcinoma in situ della cervice adeguatamente trattato, tumore della pelle diverso dal melanoma, carcinoma in situ della mammella lobulare o duttale e qualunque altro tipo di tumore invasivo (diverso dal tumore della mammella) in remissione completa da piu' di 5 anni. • Le pazienti non devono avere ricevuto chemioterapia (neo)adiuvante, endocrino terapia (neo)adiuvante o radioterapia per il carcinoma primario della mammella considerato in questo studio. • Le pazienti non devono aver partecipato ad altri studi clinici di ricerca entro le 4 settimane precedenti all’inizio del trattamento. • Le pazienti non devono essere in gravidanza o in allattamento al momento della diagnosi o della randomizzazione. Le donne in eta' fertile devono avere un test di gravidanza negativo. Se in post-menopausa , le pazienti devono essere amenorroiche da almeno 12 mesi per essere considerate non fertili. • Durante lo studio le pazienti devono utilizzare adeguate misure di contraccezione che comportano un basso tasso di fallimento (cioe' <1% all’anno) se usate regolarmente e correttamente come ad esempio contraccettivi iniettabili, impianti, alcuni dispositivi intrauterini, preservativi, astinenza sessuale o vasectomia del partner (Nota 3 della Guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. (CPMP/ICH/286/95). • Le pazienti non devono avere condizioni psicologiche, familiari, sociologiche o geografiche o condizioni cliniche gravi non controllate (per esempio storia di epilessia non controllata, disordini del sistema nervoso centrale o disabilita' psichiatrica non controllati) ritenute clinicamente significative dallo sperimentatore e che potrebbero potenzialmente precludere l’ottenimento del consenso informato o interferire con la compliance per la somministrazione orale dei farmaci o impedire la compliance al protocollo di studio o al follow up. Queste condizioni dovrebbero essere discusse con la paziente prima della registrazione in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of the MINDACT trial is to demonstrate the superiority of the molecular profiling approach over the usual clinical assessment in assigning adequate risk categories (and the need to receive adjuvant chemotherapy or not) to breast cancer patients with 0 to 3 positive lymph nodes. 2. The trial will also aim to compare a docetaxel-capecitabine regimen possibly associated with increased efficacy and reduced long-term toxicities to existing commonly used anthracycline-based chemotherapy regimens (anthracyclines followed by docetaxel for node positive). 3. The last primary objective will be to determine the best endocrine treatment strategy i.e. single agent up-front, aromatase inhibitor (AI) (letrozole) for seven years compared to the sequential endocrine strategy of 2 years of tamoxifen followed by 5 years of letrozole. |
| 1. L’obiettivo primario dello studio Mindact e' dimostrare la superiorita' di un approccio basato sul profilo molecolare rispetto alla valutazione clinica usuale nell’assegnare categorie di rischio adeguate (e la necessita' di ricevere chemioterapia adiuvante o no) a pazienti affette da tumore della mammella con 0-3 linfonodi positivi. 2. Lo studio ha anche lo scopo di confrontare un regime chemioterapico a base di docetaxel-capecitabina, possibilmente associato con un aumento di efficacia e una ridotta tossicita' a lungo termine, rispetto al regime standard di chemioterapia a base di antraci cline (antraci cline seguite da docetaxel per le pazienti con linfonodi positivi). 3. Determinare la migliore strategia di terapia endocrina cioe' una monoterapia con agente singolo sin dall`inizio, inibitore delle aromatasi (AI) (letrozolo) per sette anni, comparato con uno schema sequenziale di terapia endocrina di 2 anni di tamoxifene seguiti da 5 anni di letrozolo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| not available |
| non disponibile |
|
| E.5.2 | Secondary end point(s) |
| Comparison of the two prognostic methods: ¨ To estimate both relative (Hazard Ratio, HR) and absolute (as % at 5 years) efficacy in terms of disease free survival (DFS), distant metastasis free survival (DMFS) and overall survival (OS) of chemotherapy in the two subgroups where the clinical-pathological prognosis and the 70-gene signature molecular prognosis are discordant. ¨ To calculate overall estimates of efficacy (DFS, DMFS, OS) for each treatment strategy according to clinical-pathological prognosis and according to molecular prognosis. ¨ To estimate the percentage of patients receiving chemotherapy per each prognostic method. Gene profiling: ¨ To identify and/or validate predictive gene expression profiles of clinical response/resistance to anthracycline-based and docetaxelcapecitabine chemotherapy. ¨ The identification and validation of novel gene expression signatures predicting clinical response to sequential tamoxifen-AI versus AI alone. Chemotherapy: ¨ To compare the OS distributions associated with the 2 chemotherapy arms ¨ To determine and compare the early and late toxicities associated with each arm. Endocrine therapy: ¨ To evaluate adjuvant endocrine treatment success or failure in the subgroup of postmenopausal patients with endocrine responsive disease. ¨ To compare the safety profile of the two endocrine therapy regimens |
| Confronto di due modelli prognostici: • Stimare sia l’efficacia relativa (Hazard Ratio, HR), che assoluta (come % a 5 anni) in termini di sopravvivenza libera da malattia (DFS, Disease Free Survival), di sopravvivenza libera da metastasi a distanza (DMFS, Distant Metastasis Free Survival) e di sopravvivenza complessiva (OS, Overall Survival) della chemioterapia nei due sottogruppi in cui la prognosi clinico-patologica e la prognosi molecolare determinata con la “firma” di 70 geni sono discordanti. • Calcolare la stima complessiva dell’efficacia (DFS, DMFS, OS) per ogni strategia di trattamento secondo la prognosi clinico-patologica e secondo la prognosi molecolare. • Stimare la percentuale di pazienti che ricevono la chemioterapia per ciascun metodo prognostico. Profilo genico: 1. Identificare e/o validare il profilo di espressione genica predittivo della risposta clinica/resistenza alla chemioterapia basata sull’impiego di antracicline e sull’impiego di docetaxel-capecitabina. 2. Identificazione e validazione di una nuova `firma` dell’espressione genica che sia predittiva della risposta clinica per lo schema sequenziale Tamoxifene-AI vs solo AI. Chemioterapia: 1. Confrontare le distribuzioni di OS associate con i due bracci chemioterapici. 2. Determinare e confrontare le tossicita' precoci e tardive associate ad ogni braccio. Terapia Endocrina: 1. Valutare il successo o il fallimento del trattamento endocrino nel sottogruppo di pazienti in post-menopausa con malattia endocrino–responsiva. 2. Confrontare il profilo di sicurezza dei due regimi di terapia endocrina. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| not available |
| non disponibile |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 17 |
| 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 | 17 |
| 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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