E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early human epidermal growth factor receptor 2 (HER2) positive breast cancer. |
Carcinoma mammario HER2 positivo ad alto rischio di recidiva |
|
E.1.1.1 | Medical condition in easily understood language |
HER2-positive breast cancer is a type of breast cancer in which breast cancer cells have a protein called HER2 on their surface. |
Il carcinoma mammario HER2-positivo è un tipo di cancro al seno in cui le cellule del cancro al seno hanno una proteina chiamata HER2 sulla loro superficie. |
|
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 | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER2 positive 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 evaluate the efficacy of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine on the basis of invasive disease free survival (IDFS). |
L’obiettivo di efficacia primario di questo studio è valutare l’efficacia di atezolizumab somministrato in associazione a trastuzumab emtansine rispetto a placebo e trastuzumab emtansine sulla base del IDFS, definita come il tempo che intercorre tra la randomizzazione e la prima registrazione di uno degli eventi |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine on the basis of IDFS including second primary non breast invasive cancer, disease free survival, overall survival, distantrecurrence-free interval, the proportion of patients in each arm with clinically meaningful deterioration in global health status/quality of life (GHS/QoL) physical, role, and cognitive function as measured by scalesof the European Organisation for Research and Treatment of Cancer quality of life questionnaire for cancer, mean absolute scores and mean change from baseline scores in GHS/QoL, physical, role, cognitive function; - To evaluate safety of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumabemtansine; - To characterize pharmacokinetic profiles of atezolizumab and trastuzumab emtansine; - To evaluate immune response to atezolizumab and trastuzumab emtansine. |
Valutare efficacia di atezolizumab somministrato in associazione a trastuzumab emtansine rispetto a placebo e trastuzumab emtansine sulla base di IDFS, incluso secondo tumore primario non invasivo della mammella, sopravvivenza libera da malattia, la percentuale di pazienti in ciascun braccio con deterioramento clinicamente significativo dello stato di salute globale / qualità della vita (GHS / QoL) funzione fisica, ruolo e cognitiva misurata dalle scale del questionario sulla qualità della vita dell'Organizzazione europea per la ricerca e il trattamento del carcinoma, punteggi assoluti e variazione media rispetto ai punteggi di base in GHS / QoL, fisica, ruolo, funzione cognitiva; - Per valutare la sicurezza di atezolizumab quando somministrato in combinazione con trastuzumab emtansine rispetto a placebo e trastuzumab emtansine; - Caratterizzare i profili farmacocinetici di atezolizumab e trastuzumab emtansine; - Valutare la risposta immunitaria ad atezolizumab e trastuzumab emtansine |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- Histologically confirmed invasive breast carcinoma
- Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph node(s) at surgery after completion of neoadjuvant therapy
- Diagnosis of HER2-positive breast cancer with assessment of hormone receptor and programmed death¿ligand 1 status, as documented through central testing of a representative tumor tissue specimen
- Completion of preoperative systemic chemotherapy and HER2-directed treatment
- Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes
- An interval of no more than 12 weeks between the date of primary surgery and the date of randomization
- Eastern Cooperative Oncology Group Performance Status 0 or 1
- Screening left ventricular ejection fraction >= 50% on echocardiogram or multiple-gated acquisition scan after completion of neoadjuvant therapy and no decrease in left ventricular ejection fraction (LVEF) by more than 15% absolute points from the pre-chemotherapy LVEF. Alternatively, if the pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55% after completion of neoadjuvant therapy
- Life expectancy >= 6 months
- Adequate hematologic and end organ function
- For women of childbearing potential: agreement to remain abstinent or to use contraception, and agreement to refrain from donating eggs during the treatment period and for 5 months after the final dose of atezolizumab/placebo and for 7 months after the final dose of trastuzumab emtansine or trastuzumab
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 7 months after the final dose of trastuzumab emtansine or trastuzumab
|
• Età >= di 18 anni al momento della firma del modulo di consenso informato • Capacità di rispettare il protocollo dello studio • Carcinoma mammario invasivo istologicamente confermato • Stadio clinico alla presentazione • Diagnosi di carcinoma mammario HER2-positivo con valutazione dello stato dei recettori ormonali e dello stato di PD-L1, • Completamento della chemioterapia sistemica preoperatoria e del trattamento diretto contro HER2 • Escissione adeguata: asportazione chirurgica di tutte le lesioni clinicamente evidenti nel seno e nei linfonodi, • Un intervallo non superiore alle 12 settimane tra la data della chirurgia primaria e la data della randomizzazione. • Punteggio del performance status secondo l’Eastern Cooperative Oncology Group di 0 o 1 • Frazione di eiezione ventricolare sinistra (LVEF) allo screening >= 50% all’ecocardiogramma o all’angiocardioscintigra¿a all’equilibrio dopo il completamento della terapia neoadiuvante • Aspettativa di vita >= 6 mesi • Adeguata funzione ematologica e degli organi terminali • Per le donne potenzialmente fertili: consenso a praticare l’astinenza (astenersi dai rapporti eterosessuali) o a utilizzare metodi contraccettivi e consenso ad astenersi dal donare ovuli • Per gli uomini: consenso a praticare l’astinenza (evitare i rapporti eterosessuali) o a utilizzare misure contraccettive e consenso ad astenersi dal donare liquido seminale, |
|
E.4 | Principal exclusion criteria |
- Stage IV (metastatic) breast cancer;
- Inadequate excision;
- An overall response of disease progression according to the investigator at the conclusion of preoperative systemic therapy;
- Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons;
- History of other malignancy within 5 years prior to screening;
- History of exposure to the following cumulative doses of anthracyclines:
o Doxorubicin > 240 mg/m2;
o Epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m2;
o For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m2;
- Prior treatment with trastuzumab emtansine or atezolizumab;
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies;
- Current Grade >= 2 peripheral neuropathy;
- Dyspnea at rest;
- Cardiopulmonary dysfunction;
- Active or history of autoimmune disease or immune deficiency;
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis:
o History of radiation pneumonitis in the radiation field is permitted;
- Active tuberculosis;
- Current severe, uncontrolled systemic disease;
- Any known active liver disease;
- Major surgical procedure, other than for breast cancer, within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the study;
- Severe infection within 4 weeks prior to randomization;
- Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral antibiotics) prior to randomization;
- Prior allogeneic stem cell or solid organ transplantation;
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug and may affect the interpretation of the results, or may render the patient at high risk from treatment complications;
- Treatment with a live, attenuated vaccine within 4 weeks prior to randomization, or anticipation of need for such a vaccine during atezolizumab/placebo treatment or within 5 months after the final dose of atezolizumab/placebo;
- Treatment with investigational therapy within 28 days prior to randomization;
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization;
- Treatment with systemic immunosuppressive medication within 2 weeks prior to randomization, or anticipation of need for systemic immunosuppressive medication during study treatment;
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins;
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation;
- History of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product;
- Pregnant or breastfeeding, or intending to become pregnant during study treatment or within 5 months after the final dose of atezolizumab/placebo or within 7 months after the final dose of trastuzumab emtansine or trastuzumab, whichever occurs last.
|
• Tumore mammario di fase IV (metastatico) • Escissione inadeguata (vedere descrizione nei criteri di inclusione) • Risposta complessiva di progressione della malattia alla conclusione della terapia sistemica preoperatoria secondo il giudizio dello sperimentatore • Pazienti per i quali sarebbe raccomandata la radioterapia per il trattamento del tumore mammario, ma che presentano controindicazioni mediche al suo utilizzo • Anamnesi di altra neoplasia maligna nei 5 anni precedenti lo screening, eccetto carcinoma in situ della cervice debitamente trattato, carcinoma cutaneo non melanomatoso, tumore uterino di stadio I o DCIS • Anamnesi di esposizione alle seguenti dosi cumulative di antracicline: Doxorubicina ¿ 240 mg/m2 Epirubicina o doxorubicina liposomiale cloridrato (Myocet¿) ¿ 480 mg/m2 Per altre antracicline, esposizione equivalente a doxorubicina > 240 mg/m2 • Precedente trattamento con trastuzumab emtansine o atezolizumab • Precedente trattamento con agonisti di CD137 o con terapie di blocco del checkpoint immunitario, inclusi anticorpi terapeutici anti¿proteina 4 associata al linfocita T citotossico, anti¿PD1 e anti¿PD-L1 • Attuale neuropatia periferica di grado NCI CTCAE (Versione 5.0) >= 2 • Dispnea a riposo • Disfunzione cardiopolmonare • Malattia autoimmune o deficit immunitario attivi o in anamnesi • Presenza di anamnesi di fibrosi polmonare idiopatica, polmonite in via di organizzazione • Tubercolosi attiva • Attuale malattia sistemica grave non controllata • Qualsiasi epatopatia attiva nota, disturbi epatici autoimmuni o colangite sclerosante • Procedura chirurgica maggiore, se non per il carcinoma mammario, nelle 4 settimane precedenti la randomizzazione o necessità prevista di una procedura chirurgica maggiore durante lo studio • Infezione grave nelle 4 settimane precedenti la randomizzazione, comprese a titolo esemplificativo e non esaustivo, ricovero per complicanze di un’infezione, batteriemia, polmonite grave, infezione da SARS CoV 2, o qualsiasi infezione attiva che, secondo il parere dello sperimentatore, potrebbe pregiudicare la sicurezza del paziente • Trattamento con antibiotici a scopo terapeutico nelle 2 settimane (antibiotici e.v.) o nei 5 giorni (antibiotici orali) precedenti la randomizzazione • Precedente trapianto allogenico di cellule staminali o di organi solidi • Qualsiasi altra malattia, disfunzione metabolica • Trattamento con un vaccino vivo attenuato nelle 4 settimane precedenti la randomizzazione • Trattamento con una terapia sperimentale nei 28 giorni precedenti la randomizzazione • Trattamento con agenti immunostimolatori Trattamento con medicinali immunosoppressori per via sistemica • Anamnesi di gravi reazioni allergiche anafilattiche agli anticorpi • Nota ipersensibilità ai prodotti di cellule di ovaio di hamster cinese • Anamnesi di intolleranze, incluse reazioni all’infusione di grado 3 o 4 • Gravidanza o allattamento o pianificazione di una gravidanza durante il trattamento sperimentale o nei 5 mesi successivi all’ultima dose di atezolizumab/placebo o nei 7 mesi successivi all’ultima dose di trastuzumab emtansine o trastuzumab |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Invasive disease-free survival |
Sopravvivenza libera da malattia invasiva |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 6 years |
Approssimativamente 6 anni |
|
E.5.2 | Secondary end point(s) |
1. Invasive disease-free survival including second primary non breast invasive cancer;
2. Disease-free survival;
3. Overall survival;
4. Distant recurrence-free interval;
5. The proportion of patients in each arm with clinically meaningful deterioration in GHS/QoL physical, role, and cognitive function as measured by scales of the European Organisation for Research and Treatment of Cancer quality of life questionnaire for cancer (EORTC QLQ C30);
6. Mean absolute scores and mean change from baseline scores in GHS/QoL, physical, role, and cognitive function, as assessed using the EORTC QLQ C30;
7. Incidence and severity of adverse events;
8. Maximum and minimum serum concentrations for atezolizumab and trastuzumab emtansine;
9. Incidence of anti-drug antibodies (ADAs) to atezolizumab and to trastuzumab emtansine at specified timepoints. |
1. Sopravvivenza libera da malattia invasiva incluso il secondo tumore primario non invasivo al seno; 2. Sopravvivenza libera da malattia; 3. Sopravvivenza globale; 4. Intervallo libero da recidiva distante; 5. La proporzione di pazienti in ciascun braccio con deterioramento clinicamente significativo della funzione fisica, di ruolo e cognitiva di GHS / QoL misurata dalle scale del questionario sulla qualità della vita per il tumore dell'Organizzazione europea per la ricerca e il trattamento del tumore (EORTC QLQ C30); |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-9. Approximately 6 years; for overall survival approximately 10 years. |
1-9 approssimativamente 6 anni; 10 anni per la sopravvivenza globale |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
immunogenicity, biomarker, exploratory health status (patient-reported outcomes). |
immunogenicity, biomarker, exploratory health status (patient-reported outcomes). |
|
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 189 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Poland |
Portugal |
Romania |
Spain |
United Kingdom |
Czechia |
|
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 | 10 |
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 | 10 |
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 |