| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple negative breast cancer |
| Tumore mammario triplo-negativo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple negative breast cancer |
| Tumore mammario triplo-negativo |
|
| 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) |
|
| 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 whether 1 year of adjuvant Avelumab improves disease-free
survival (DFS) compared to observation in patients with high-risk primary triple
negative breast cancer (all comers, unselected for PD-L1 status) who have
completed treatment with curative intent including surgery of the primary
tumor and neo- or adjuvant chemotherapy.
- to determine whether 1 year of adjuvant Avelumab improves disease-free
survival (DFS) compared to observation in PD-L1-positive (as determined by a
companion diagnostic test under development) patients with high-risk primary
triple negative breast cancer who have completed treatment with curative
intent including surgery of the primary tumor and neo- or adjuvant
chemotherapy. |
Obiettivi di efficacia co-primari:
- determinare se 1 anno di terapia con Avelumab adiuvante prolunghi la sopravvivenza libera da malattia rispetto alla sola osservazione, in pazienti con carcinoma mammario triplo-negativo ad alto rischio che abbiano completato il trattamento ad intento curativo, comprendente l’intervento chirurgico e la chemioterapia adiuvante o neodiuvante (Gruppo A [intervento chirurgico seguito da chemioterapia adiuvante] e Gruppo B [chemioterapia neoadiuvante seguita da intervento chirurgico] combinati).
- determinare se 1 anno di trattamento con Avelumab adiuvante migliori la sopravvivenza libera da malattia rispetto alla sola osservazione in pazienti con carcinoma mammario triplo-negativo ad alto rischio, che abbiano completato il trattamento ad intento curativo, comprendente chemioterapia neoadiuvante seguita da intervento chirurgico (Strato B) |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy
- to determine whether Avelumab improves overall survival (OS) compared to observation in patients with high-risk primary triple negative breast cancer who have completed treatment with curative intent including surgery of the primary tumor and neo- or adjuvant chemotherapy.
SAFETY OBJECTIVES
- to assess the overall safety of Avelumab administered as adjuvant treatment
in patients with high-risk primary triple negative breast cancer who have
completed treatment with curative intent including surgery of the primary
tumor and neo- or adjuvant chemotherapy.
EXPLORATORY OBJECTIVES
- to explore molecular, circulating and microbiological biomarkers , in tumor tissue,
plasma and fecal samples that may be relevant to the mechanism of action of,
or efficacy/resistance to avelumab. |
Efficacia
determinare se Avelumab migliori la sopravvivenza globale rispetto alla sola osservazione in pazienti con carcinoma mammario triplo-negativo che abbiano completato il trattamento ad intento curativo,
determinare se 1 anno di terapia con Avelumab adiuvante migliori la sopravvivenza libera da malattia rispetto alla sola osservazione in pazienti con carcinoma mammario triplo-negativo ad alto rischio, con positività per PD-L1, e che abbiano completato il trattamento ad intento curativo
SICUREZZA
determinare la sicurezza globale di Avelumab somministrato come trattamento adiuvante in pazienti con carcinoma mammario triplo-negativo che abbiano completato il trattamento ad intento curativo,
ESPLORATORI
esplorare marcatori molecolari circolanti e microbiologici nel tessuto tumorale, plasma e campioni fecali che possano essere rilevanti per il meccanismo d’azione o nel determinare l’efficacia/la resistenza ad Avelumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female subjects aged > 18 years
Signed written informed consent before any trial-related procedure is undertaken that is not part of the standard patient management
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Non-metastatic, histologically confirmed primary invasive breast carcinoma
Triple negative breast cancer: hormone receptor negative (ER < 10% and PgR < 10%) and HER2 negative (IHC 0/1+ or ISH non-amplified), as defined by the local pathology laboratory. In case of discordance between pre-operative core-biopsy and the surgical sample, the receptor assessment performed on the surgical sample has to be considered for inclusion criteria evaluation.
Patients must have completed treatment with curative intent including: surgery, adjuvant chemotherapy.
Adequately excised: patients must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy.
Pathological node staging (Union for International Cancer Control–American Joint Committee on Cancer [UICC/AJCC] 7th edition): patients must have had axillary lymph node dissection for evaluation of pathologic nodal status. Only patients with
- if 4 or more metastatic lymph nodes, any pT
- if 1 to 3 metastatic lymph nodes, pT >2 cm
- if no metastatic lymph nodes, pT >5 cm
Patients must have completed adjuvant chemotherapy including at least 3 courses of an anthracycline agent and 3 courses of a taxane agent. Patients who received dose-dense regimens and those who received carboplatin as part of the adjuvant treatment are eligible.
No more than 10 weeks may elapse between the completion of last adjuvant treatment (adjuvant chemotherapy or radiotherapy if indicated) and randomization.
Normal organ and marrow function
a. White blood count (WBC) greater than or equal to 2.5 x109/L
b. Absolute neutrophil count (ANC) greater than or equal to 1.5 x109/L
c. Absolute lymphocyte count greater or equal to 0.5 x109/L
d. Platelet count greater than or equal to 100 x109/L
e. Hemoglobin greater than or equal to 9 g/dL
f. Serum creatinine less or equal to 1.25 x the upper limit of laboratory normal range (ULN)
g. Adequate hepatic function defined by a total bilirubin level less or equal to 1.5 x ULN range and AST and ALT levels less or equal than 2.5 x ULN for all subjects. For patients with known Gilbert’s syndrome, total bilirubin levels less or equal than 2 x ULN range (with direct bilirubin less than ULN) will be accepted.
Highly effective contraception (i.e. methods with a failure rate of less than 1 % per year) for both male and female subjects if the risk of conception exists (Note: The effects of the trial treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception, defined in Appendix A or as stipulated in national or local guidelines. Highly effective contraception must be used 28 days prior to first trial treatment administration, for the duration of trial treatment, and at least for 60 days after stopping trial treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately).
Ability to understand and willingness to sign a written informed consent.
Clinical stage at presentation: T1–4, N0–3, M0 (Exception: Patients with T1a/bN0 tumors at presentation will not be eligible).
Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes on the surgical specimen obtained after preoperative therapy (ypT1micN0, ypT1micN0i+, ypT0N0i+ will be excluded). |
Gruppo A/B
-Soggetti di sesso maschile o femminile con più di 18 anni di età
-Firma del consenso informato
-(ECOG) performance status 0 o 1
-Carcinoma mammario primitivo, confermato istologicamente, non metastatico
-Carcinoma mammario triplo-negativo
-Disponibilità di blocchetti fissati in formalina e inclusi in paraffina contenenti tessuto tumorale, o di almeno 7 vetrini in bianco
-Escissione adeguata
-A Stadiazione patologica linfonodale.Saranno eleggibili solo i pazienti con
Se 4 o più linfonodi metastatici, qualsiasi pT
o Se da 1 a 3 linfonodi metastatici, pT>2 cm
o Se assenza di linfonodi metastatici, pT >5 cm
-I pazienti devono aver completato la chemioterapia adiuvante con almeno 3 cicli di un’antraciclina e 3 cicli di un taxano
-Non devono essere trascorse più di 10 settimane tra il completamento dell’ultimo trattamento adiuvante
-Funzione d’organo e midollare:
a.Conta dei globuli bianchi maggiore o uguale a 2.5 x109/L
b.Conta dei neutrofili assoluta maggiore o uguale a 1.5 x109/L
c.Conta linfocitaria assoluta maggiore o uguale a 0.5 x109/L
d.Conta piastrinica maggiore o uguale a 100 x109/L
e.Emoglobina maggiore o uguale a 9 g/dL
f.Creatinina sierica inferiore o uguale a 1.25 x il limite superiore del range di normalità adottato dal laboratorio (ULN)
g.Funzione epatica adeguata, definita da livelli di bilirubina totale inferiori o uguali a 1.5 x ULN e livelli di AST e ALT inferiori o uguali a 2.5 x ULN per tutti i soggetti. Per i pazienti con una sindrome di Gilbert nota, saranno accettati livelli di bilirubina totale inferiori o uguali a 2 x ULN (con la bilirubina diretta inferiore a ULN)
-Contraccezione ad alta efficacia
-Capacità di comprendere e di firmare volontariamente il consenso informato
-B Stadio clinico alla presentazione: T1–4, N0–3, M0 (Eccezioni: non saranno eleggibili pazienti con neoplasia T1a/b N0 alla presentazione)
-B Evidenza istopatologica di carcinoma infiltrante residuo nella mammella e/o nei linfonodi ascellari sul campione chirurgico ottenuto dopo chemioterapia neoadiuvante (ypT1micN0, ypT1micN0i+, ypT0N0i+ saranno esclusi) |
|
| E.4 | Principal exclusion criteria |
Stage IV breast cancer.
History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed within 10 years.
Synchronous bilateral breast cancer, unless both tumors confirmed as triple negative disease.
History of non-breast malignancies within the 5 years prior to study entry, except for the following: Carcinoma in situ (CIS) of the cervix, CIS of the colon, Basal cell and squamous cell carcinomas of the skin.
Prior organ transplantation, including allogeneic stem-cell transplantation.
Prior or concomitant treatment with any other investigational agents.
Prior therapy with any antibody / drug targeting T-cell coregulatory proteins such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Concurrent anticancer treatment
Major surgery for any reason, within 4 weeks of randomization and / or if the subject has not fully recovered from the surgery within 4 weeks of randomization.
Concomitant treatment with all herbal (alternative) remedies with immunostimulating properties or known to potentially interfere with major organ function.
Subjects receiving immunosuppressive agents for any reason should be tapered off these drugs before initiation of the trial treatment (with the exception of subjects with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to = 10 mg prednisone daily).
Significant acute or chronic infections including, among others:
a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses = 10 mg or equivalent prednisone per day.
c. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
Administration of steroids through a route known to result in a minimal systemic exposureare acceptable.
Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the daily dose after 14 days will be = 10 mg per day of equivalent prednisone.
Known severe hypersensitivity reactions to monoclonal antibodies , any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident /stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class = II), or serious uncontrolled cardiac arrhythmia requiring medication.
All other significant diseases which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment.
Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines.
Known alcohol or drug abuse.
Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (except for grade 2 radiodermatitis and grade 2 neuropathy).
Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods.
No invasive residual disease in the breast and axilla at pathological examination after neoadjuvant chemotherapy. ypT1micN0, ypT1micN0i+, ypT0N0i+ will also be excluded. |
Carcinoma mammario stadio IV.
Storia di precedente carcinoma mammario omo- o contro-laterale entro 10 anni.
Carcinoma mammario bilaterale sincrono, a meno che entrambi triplo-negativi.
Storia di neoplasie maligne non mammarie entro i 5 anni precedenti all’ingresso nello studio, eccezion fatta per: carcinoma in situ della cervice uterina, carcinoma in situ del colon, carcinoma basocellulare o squamocellulare della cute.
Precedente trapianto d’organo, compreso il trapianto allogenico di cellule staminali.
Trattamento precedente o concomitante con qualsiasi altro agente in fase di investigazione.
Precedente trattamento con qualsiasi anticorpo/farmaco agente nei confronti di proteine co-regolatorie delle cellule T (checkpoint immunitari) come PD-1, PD-L1 o CTLA4.
Trattamenti antitumorali concomitanti
Chirurgia maggiore entro 4 settimane dalla randomizzazione e/o in caso in cui il soggetto non si sia completamente ripreso da un intervento chirurgico entro 4 settimane dalla randomizzazione.
Trattamenti concomitanti con rimedi erboristici dotati di proprietà immunostimolanti
I pazienti che per qualsiasi motivo stanno assumendo agenti immunosoppressivi
Infezioni significative acute o croniche
Patologie autoimmuni attive
Reazioni severe da ipersensibilità note agli anticorpi monoclonali , storia di anafilassi o di asma incontrollata
Malattia cardiovascolare clinicamente significativa
Qualsiasi condizione psichiatrica che potrebbe impedire al soggetto di comprendere o di fornire un consenso informato.
Tossicità persistente correlata al precedente trattamento di grado >1
Gravidanza o allattamento in atto. Rifiuto di adottare metodi contraccettivi efficaci
Assenza di malattia infiltrante residua a livello della mammella e/o dei linfonodi ascellari alla valutazione istopatologica dopo chemioterapia neoadiuvante. Saranno inoltre esclusi: ypT1micN0, ypT1micN0i+, ypT0N0i+. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| DFS in the whole population |
| sopravvivenza libera da malattia nella popolazione totale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease-free survival will be defined as the time from randomization to loco-regional invasive recurrence, second primary invasive breast cancer, other second primary cancer (excluding in-situ cancers), distant metastasis or death from any cause. |
| Sopravvivenza libera da malattia: definita come l’intervallo di tempo tra la randomizzazione e la recidiva invasiva loco-regionale, un secondo carcinoma mammario primario, una seconda neoplasia maligna primitiva (escluse le neoplasie in situ), metastasi a distanza o morte per qualsiasi causa. |
|
| E.5.2 | Secondary end point(s) |
| Safety profile |
| Profilo di sicurezza |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients will be followed 5 years after randomization;nature, incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will be collected. Incidence of and reasons for study drug dose interruption or reduction and discontinuation will be collected. Toxicities will be graded using NCI -CTCAE v. 4.03. |
I pazienti verranno seguiti per 5 anni dalla randomizzazione
Per determinare il profilo di sicurezza, saranno raccolte la natura, l’incidenza e la severità degli eventi avversi (AEs) e degli avventi avversi severi (SAEs). Saranno inoltre documentate l’incidenza di e la ragione per l’interruzione di dose, la riduzione o la cessazione del farmaco oggetto di studio. Infine ad ogni tossicità verrà assegnato un grado secondo il sistema NCI -CTCAE v. 4.03.
|
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Osservazione secondo Linee guida Nazionali ed Internazionali |
| Observation as per National and international guidelines |
|
| 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 | 66 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 | Yes |
| 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 | 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 |
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