| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Breast cancer is the most common form of cancer among women in North America, Europe and Latin America. Beacause nearly 80% of breast cancers are endocrine-responsive tumors, the majority of patients candidates for adjuvant chemotherapy (CT) are also candidates for endocrine therapy (ET).The optimal timing (i.e. concomitant vs sequential administration) for the integration of these two treatments has not been clearly defined yet. |
| Il tumore della mammella e' la piu' frequente neoplasia tra le donne del nord America, dell'Europa e dell'America latina. In considerazione del fatto che l'80% dei tumori della mammella sono ormonosensibili, la maggioranza delle pazienti candidate per una chemioterapia adiuvante sono altresi' candidate ad una terapia endocrina. La tempistica ottimale (somministrazione concomitante vs sequenziale) non e' ancora stata chiarita con precisione. |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer is the most common form of cancer among women. For patients candidated for adjuvant chemotherapy and endocrine therapy the optimal timing for their has not been clearly defined yet. |
| Il tumore della mammella e' la piu' frequente neoplasia tra le donne. Per le donne candidate a chemioterapia e ormonoterapia, la tempistica ottimale della loro somministrazione non e' ancora chiara. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 evaluate the relative efficacy of sequential as compared to concurrent administration of chemotherapy and aromatase inhibitors in patients with early breast cancer in the prevention of disease recurrence. |
| Valutare l'efficacia della somministrazione sequenziale verso la concomitante della chemioterapia e degli inibitori dell'aromatasi in pazienti con tumore della mammella operato nella prevenzione della recidiva di malattia. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the relative efficacy of the two treatment strategies on overall mortality, local relapses, distant relapses, and to compare their toxicity. |
| Valutare l'efficacia relativa delle due strategie terapeutiche sulla sopravvivenza globale, le recidive locali e a distanza, e confrontare la loro tossicita'. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women with histological diagnosis of invasive breast cancer completely removed by surgery, any T, any N.
- Postmenopausal status defined by at least one of the following conditions:
1. Aged ≥ 60
2. Aged 45-59 and satisfying one or more of the following criteria
• amenorrhea for ≥12 months and intact uterus;
• amenorrhea for <12 months and FSH within the
postmenopausal range, including:
pts with hysterectomy
pts who have received HRT
pts with chemotherapy-induced amenorrhea
3. bilateral oophorectomy at any age >18 years.
- Primary tumor positive for ER and/or PgR (≥1% tumor cells positive by
immunohistochemistry or ≥ 10 fmol/mg cytosol protein by ligand binding assay).
- Patients who are prescribed 5 years of endocrine therapy with an AI
- Indication for adjuvant chemotherapy- Patients with HER-2 positive tumors are eligible provided that they are prescribed
trastuzumab according to registered schedule.
- Signed informed consent.
|
- Donne con diagnosi istologica di carcinoma mammario invasivo rimosso radicalmente dalla chirurgia, qualsiasi T, qualsiasi N.
- stato postmenopausale definito da almeno una delle seguenti condizioni:
1. eta' ≥ 60
2. eta' 45-59 che soddisfino uno o piu' dei seguenti criteri
• amenorrea per ≥12 mesi e utero conservato;
• amenorrea per <12 mesi e FSH all'interno del range menopausale, che includa:
pz isterectomizzate
pz che hanno ricevuto terapia ormonale sostitutiva
pz con amenorrea indotta da chemioterapia
3. ooforectomia ad ogni eta' >18 anni
- tumore primitivo positivo per ER e/o PgR (≥1% di cellule positive all'immunoistochimica o ≥ 10 fmol/mg cytosol protein attraverso il ligand binding assay).
- pazienti a cui viene prescritta una terapia endocrina con inibitori dell’aromatasi per 5 anni
- indicazione alla chemioterapia adiuvante. Le pazienti con malattia Her2 positiva sono eleggibili se viene loro prescritto trastuzumab con da indicazioni
- consenso informato scritto
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| E.4 | Principal exclusion criteria |
- HRT currently assumed or during the month before randomization
- Recurrent or metastatic disease
- HER-2 positive tumors if treatment with trastuzumab is considered not appropriate/feasible
- Concurrent illness that contraindicate adjuvant endocrine treatment and/or chemotherapy
- Patients who have received TAM as part of any breast cancer prevention trial
- Previous history of invasive breast cancer or other invasive malignancy within
the previous 10 years, other than squamous or basal cell carcinoma of the skin
or carcinoma in situ of the cervix, adequately cone biopsied
- Concomitant severe disease which would place the patient at unusual risk
- Concurrent treatment with experimental drugs
- Patients treated with systemic investigational drugs within the past 30 days
|
-Terapia ormonale sostitutiva assunta al momento o un mese prima della randomizzazione
- Malattia recidivata o metastatica
- Malattia HER-2 positiva se il trattamento con trastuzumab e’ considerate non appropriato/fattibile
- Patologie concomitanti che controindichino una terapia adiuvante endocrina o chemioterapia
- Pazienti che hanno ricevuto il tamoxifene all’interno di studi clinici di chemioprevenzione
-Precedente storia di carcinoma invasive della mammella o altri tumori invasivi nei 10 anni precedenti, con l’eccezione del carcinoma squamoso o a cellule basali della cute e del carcinoma in situ della cervice uterina adeguatamente sottoposto a conizzazione
- Malattie severe concomitanti che porrebbero il paziente ad un rischio inadeguato
- Trattamenti concomitanti con farmaci sperimentali
- Pazienti trattati con farmaci sperimentali nei 30 giorni precedenti
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
According to the STEEP system (Hudis et al. J Clin Oncol 2007; 25:2127-2132) the primary endpoint will be the so called DFS, defined as time elapsing between the date of randomization and the date of one of the following events, whichever occurs first
Local Recurrence of disease
Regional recurrence of disease
Distant recurrence of disease
Contralateral invasive or intraductal breast cancer
Second primary malignancy other than breast
Death for any cause
|
In accordo con lo STEEP system (Hudis et al. J Clin Oncol 2007; 25:2127-2132) l' endpoint primario e' la sopravvivenza libera da malattia definita come il tempo intercorrente tra la data della randomizzazione e uno dei seguenti eventi:
recidiva locale di malattia
recidiva regionale di malattia
recidiva a distanza di malattia
carcinoma mammario controlaterale invasivo o intraduttale
secondo tumore maligno
decesso per ogni causa |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study hypothesis is that concurrent administration of chemotherapy and endocrine therapy will be associated with a 20% relative reduction in the hazard of recurrence, with a 7% absolute increase in 10-year DFS, which is estimated to be 50% in the control group.
For a type I error level of .05 (two sided) and 80% power, it is necessary to observe 635 events. To this aim, 900 patients per arm will be recruited over a 3-year period (a total of 1800 patients), for a recruitment rate of 600 subjects per year, which is considered feasible. No interim analyses will be performed; the final analysis will be conducted when 635 events have been observed, presumably after 5.5 years of follow-up.
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L’ipotesi dello studio e’ che la somministrazione concomitante della chemioterapia e dell’endocrinoterapia sia associata ad una riduzione relative del 20% nel rischio di recidiva con un 7% di incremento assoluto nella sopravvivenza libera da malattia a 10 anni, che si stima essere 50% nel gruppo di controllo.
Per un livello di errore di primo tipo pari a 0.05 (2 code) e una potenza dell’80%, e’ necessario osservare 635 eventi.
Per questo obiettivo e’ necessario arruolare 900 pazienti per braccio per un periodo di tre anni (1800 pazienti), per un tasso di arruolamento di 600 pazienti/anno che e’ considerato fattibile.
Non sono previste analisi ad interim; l’analisi finale sara’ condotta quando saranno osservati 635 eventi, presumibilmente dopo 5.5 anni di follow up.
|
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints will be:
- the Overall Survival (OS) defined as time elapsing between the date of randomization and the date of death for any cause
- all the other outcomes defined within the STEEP system (i.e. IDFS, DDFS, DRFS, RFS, Recurrence-free interval, Breast cancer-free interval, Distant recurrence-free interval – as reported in: Hudis et al. J Clin Oncol 2007; 25:2127-2132).
-safety: clinical and laboratory toxicities will be graded according to NCI criteria CTCAE (Common Terminology Criteria for Adverse Events of National Cancer Institute v.4.02). The adverse events witch are not reported in NCI criteria will be graded as: mild (1), moderate (2), severe (3), and life threatening (4). |
Gli endpoint secondari dello studio sono:
- sopravvivenza globale definita come il tempo dalla data di randomizzazione e la data di morte per ogni causa
-tutti gli altri endpoint a parte la sopravvivenza libera da malattia
definiti dallo STEEP system (per esempio IDFS, DDFS, DRFS, RFS, Recurrence-free interval, Breast cancer-free interval, Distant recurrence-free interval – come riportato da : Hudis et al. J Clin Oncol 2007; 25:2127-2132).
-tossicita': la tossicita' clinica e di laboratorio sara' valutata attraverso i criteri CTCAE (Common Terminology Criteria for Adverse Events of National Cancer Institute v.4.02) del NCI.
Gli eventi avversi non riportati nei criteri dell'NCI saranno valutati come segue: lieve (1), moderato (2), severo (3), a rischio di vita (4). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See timepoints of evaluation for primary endpoint |
| vedi tempistica valutazione dell'obiettivo primario |
|
| 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 | 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 | No |
| 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 | No |
| 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) | No |
| 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
| 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 | 110 |
| 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
|
The study hypothesis is that concurrent administration of chemotherapy and endocrine therapy will be associated with a 20% relative reduction in the hazard of recurrence, with a 7% absolute increase in 10-year DFS, which is estimated to be 50% in the control group. The final analysis will be conducted when 635 events have been observed, presumably after 5.5 years of follow-up.
|
L’ipotesi dello studio e’ che la somministrazione concomitante della chemioterapia e dell’endocrinoterapia sia associata ad una riduzione relativa del 20% nel rischio di recidiva con un 7% di incremento assoluto nella sopravvivenza libera da malattia a 10 anni, che si stima essere 50% nel gruppo di controllo.
L’analisi finale sara’ condotta quando saranno osservati 635 eventi, presumibilmente dopo 5.5 anni di follow up.
|
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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 | 13 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 3 |
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