E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urothelial Carcinoma, locally advanced or metastatic |
CarcinomaUroteliale, localmente avanzato o metastatico |
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E.1.1.1 | Medical condition in easily understood language |
Urothelial cancer is a type of cancer that affects the urinary tract. It includes cancer of the bladder, ureters, and renal pelvis |
carcinoma uroteliale |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate efficacy of atezolizumab (Atez) plus platinum-based chemotherapy vs. placebo plus platinum-based chemotherapy based on progression-free survival (PFS) and overall survival (OS) ¿ To evaluate efficacy of Atez monotherapy compared vs. placebo plus platinum-based chemotherapy on the basis of OS
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-L¿obiettivo primario di efficacia dello studio ¿ valutare l¿efficacia di atezolizumab + chemioterapia a base di platino rispetto a placebo + chemioterapia a base di platino sulla base sopravvivenza libera da progressione (progression-free survival, PFS) e sopravvivenza globale (overall survival, OS). -Un altro obiettivo primario di efficacia ¿ valutare l¿efficacia di atezolizumab in monoterapia rispetto a placebo + chemioterapia a base di platino in funzione della OS |
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E.2.2 | Secondary objectives of the trial |
¿ To evaluate efficacy of Atez given as either monotherapy or in combination with platinum-based chemotherapy vs. placebo in combination with platinum-based chemotherapy based on objective response rate (ORR), duration of response (DOR), OS rate, PFS rate, time to deterioration in global health status and in physical function as measured by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QLQ) Questionnaire Core 30 ¿ Investigator-assessed PFS for Atez monotherapy vs. placebo plus platinum-based chemotherapy ¿ To evaluate safety and tolerability of Atez given as either monotherapy or in combination with platinum-based chemotherapy vs. placebo plus platinum-based chemotherapy ¿ To characterize pharmacokinetics (PK) of Atez when administered as monotherapy or in combination with platinum-based chemotherapy in patients who are treatment-naive ¿ To evaluate immune response to Atez as monotherapy and in combination with platinum-based chemotherapy |
L¿obiettivo secondario di efficacia dello studio ¿ valutare l¿efficacia di atezo somministrato in monoterapia o in combinazione con chemio a base di platino rispetto a placebo in combinazione con chemio a base di platino sulla base dei seguenti endpoint: Tasso di risposta obiettiva, Durata della risposta, Tasso di OS e PFS, Tempo al deterioramento delle condizioni generali di salute e della funzionalit¿ fisica valutato mediante il questionario QLQ-C30 dell¿EORTC.PFSvalutato dallo sperimentatore per Atez monoterapia vs placebo pi¿ la chemio a base di platino. L¿obiettivo di sicurezza dello studio ¿ valutare la sicurezza e la tollerabilit¿ di atezo somministrato in monoterapia o in combinazione con chemio a base di platino rispetto a placebo in combinazione con chemio a base di platino.-caratterizzare il profilo farmacocinetico di atezolizumab somministrato in monoterapia o in combinazione con chemioterapia a base di platino in paz. naive. -valutare la risposta immunitaria nei trattamen |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years - Considered to be eligible to receive platinum-based chemotherapy, in the investigator's judgment - Eastern Cooperative Oncology Group performance status of <= 2 - Histologically documented, locally advanced (T [tumor] 4b, any N [nodes]; or any T, N 2-3) or metastatic urothelial carcinoma (mUC) (M [metastasized] 1, Stage IV) - Representative formalin-fixed paraffin-embedded tumor specimens in paraffin blocks or at least 15 unstained slides - No prior chemotherapy for inoperable locally advanced or mUC - Ineligible for cisplatin-based chemotherapy - Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 - Adequate hematologic and end-organ function - For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of carboplatin , cisplatin, or gemcitabine or for 5 months after the last dose of Atez - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of carboplatin and or gemcitabine, and/or cisplatin
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- Età >= 18 anni -Idoneità al trattamento con una chemioterapia a base di platino secondo il giudizio dello sperimentatore - Performance status secondo l’Eastern Cooperative Oncology Group (ECOG) <= 2 - Carcinoma uroteliale localmente avanzato (T4b, ogni N o qualsiasi T, N 2-3) o metastatico (M1, stadio IV) documentato dall’esame istologico - Campioni tumorali rappresentativi fissati in formalina e inclusi in paraffina (formalin-fixed paraffin-embedded, FFPE) in blocchi di paraffina o in almeno 15 vetrini non colorati - Nessuna chemioterapia precedente per carcinoma uroteliale localmente avanzato o metastatico inoperabile. - Mancata idoneità (ineleggibilità) alla chemioterapia a base di cisplatino. - Malattia misurabile secondo i criteri RECIST v1.1 - Adeguata funzionalità ematologica, epatica e renale. - Per le donne in età fertile: consenso a praticare l’astinenza (astensione dai rapporti sessuali) o ad adottare metodi contraccettivi che garantiscano un tasso di insuccesso <1% all’anno durante il periodo di trattamento e per almeno 6 mesi dopo l’ultima dose di carboplatino cisplatino o gemcitabina oppure per 5 mesi dopo l’ultima dose di atezolizumab. - . Per gli uomini: consenso a rimanera astinenti (astenersi darapporto sessuale eterosessuali) o utilizzare metodi contraccettivi e consenso ad astenersi dalla donazione di sperma entrambe le opzioni traducono in un tasso di fallimento di <1% per anno durante il periodo di trattamento e per almeno 6 mesi dopo l’ultima dose di gemcitabina e/o carboplatino e/o cisplatino. |
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E.4 | Principal exclusion criteria |
- Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment - Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrollment - Active or untreated central nervous system metastases as determined by computed tomography or magnetic resonance imaging evaluation during screening and prior radiographic assessments - Leptomeningeal disease - Uncontrolled hypercalcemia, tumor-related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures - Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1 General Medical Exclusions: - Life expectancy of < 12 weeks - Pregnant or lactating, or intending to become pregnant during the study - Serum albumin < 25 gram per liter Exclusion Criteria Related to Atezolizumab: - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - History of autoimmune disease - Patients with prior allogeneic stem cell or solid organ transplantation - History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis - Significant cardiovascular disease - Known left ventricular ejection fraction < 40% - Positive test for HIV - Active hepatitis B or hepatitis C, tuberculosis - Severe infections within 4 weeks prior to randomization - Therapeutic oral or intravenous antibiotics within 2 weeks prior to randomization - Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 - Prior treatment with Cluster of Differentiation (CD) 137 agonists, anti- cytotoxic T-lymphocyte-associated protein (CTLA)-4, anti- programmed cell death protein (PD)-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents - Treatment with systemic immunostimulatory agents, systemic corticosteroids or othercorticosteroids or other systemic immunosuppressive medications Exclusion Criteria Related to Gemcitabine: - Known hypersensitivity to gemcitabine Exclusion Criteria Related to Carboplatin: - History of severe allergic reactions to cisplatin or other platinumcontaining compounds - Severe bone marrow depression or significant bleeding Exclusion Criteria Related to Cisplatin: - Patients with preexisting renal impairment - Patients with myelosuppresion or hearing impairment - History of allergic reactions to cisplatin or other platinum-containing compounds |
- Qualsiasi trattamento antitumorale approvato, ivi incluse chemioterapia o terapia ormonale, nelle 3 settimane precedenti all’inizio del trattamento in studio. - Trattamento con qualsiasi altro agente sperimentale o partecipazione a un altro studio clinico con intento terapeutico nei 28 giorni precedenti all’arruolamento - Metastasi attive o non trattate a carico dell’SNC rilevate mediante tomografia computerizzata o risonanza magnetica durante lo screening e prima delle valutazioni radiografiche - Malattia leptomeningea -Versamento pleurico non controllato, versamento pericardico o ascite che necessita di ricorrenti procedure di drenaggio - Dolore non controllato correlato al tumore - Neoplasie maligne diverse dal carcinoma uroteliale nei 5 anni precedenti al Giorno 1 del Ciclo 1
Criteri di esclusione generali di natura medica: - Aspettativa di vita < 12 settimane - Gravidanza o allattamento, o intenzione di iniziare una gravidanza durante lo studio • Albumina sierica <25 g/l. Criteri di esclusione correlati ad atezolizumab: - Anamnesi positiva per reazioni allergiche o anafilattiche severe, oppure altre reazioni di ipersensibilità agli anticorpi chimerici o umanizzati, o alle proteine di fusione - Anamnesi positiva per malattia autoimmune - Pazienti precedentemente sottoposti a trapianto allogenico di cellule staminali o di organi solidi - Anamnesi positiva per fibrosi polmonare idiopatica , polmonite indotta da farmaci, polmonite in organizzazione o evidenza di polmonite attiva alla tomografia computerizzata - Cardiovasculopatia significativa - Frazione di eiezione del ventricolo sinistro <40% - Positività al test dell’HIV - Epatite B attiva o epatite C, tubercolosi attiva - Trattamento con antibiotici terapeutici orali o e.v. nelle 2 settimane precedenti alla randomizzazione - Somministrazione di un vaccino vivo attenuato nelle 4 settimane precedenti al Giorno 1 del Ciclo 1 - Trattamento precedente con agonisti del recettore CD137, anticorpi terapeutici anti-CTLA-4, anti-PD-1, anti-PD-L1 o agenti mirati a determinati pathway - Trattamento con immunostimolanti sistemic, con corticosteroidi sistemici o altri immunosoppressori sistemici Criteri di esclusione correlati a gemcitabina: - Ipersensibilità nota a gemcitabina Criteri di esclusione correlati al carboplatino: - Storia di gravi reazioni allergiche a cisplatino o altri composti contenenti platino -Depressione midollare grave o sanguinamento significativo Criteri di esclusione relativi a cisplatino: - Pazienti con insufficienza renale preesistente - Pazienti con myelosuppresion o danni all'udito - La storia di reazioni allergiche al cisplatino o ad altri composti contenenti platino
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E.5 End points |
E.5.1 | Primary end point(s) |
1. PFS as assessed by the investigator using RECIST v1.1 (Atez plus chemotherapy vs. placebo plus chemotherapy arms only) 2. OS (Atez plus chemotherapy vs. placebo plus chemotherapy arms only) 3. OS (Atez monotherapy vs. placebo plus platinum-based chemotherapy) |
1. PFS come valutato dallo sperimentatore utilizzando RECIST v1.1 (Solo per i bracci di trattamento Atez più chemioterapia vs placebo più chemioterapia ) 2. OS (Solo per i bracci di trattamento Atez più chemioterapia vs placebo più chemioterapia ) 3. OS (Atez monoterapia vs placebo più chemioterapiaa base di platino) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to 44 months |
1-3. Fino a 44 mesi |
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E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) 2. Duration of Response (DOR) 3. Independent Review Facility -PFS 4. Investigator assessed PFS using RECIST v1.1 (Atezo monotherapy vs. placebo plus platinum-based chemotherapy) 5. OS rate 6. PFS rate 7. Time to deterioration in global health status and physical function as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QLQ) Questionnaire Core 30 Safety 8. Incidence, nature and severity of adverse events 9. Changes in vital signs and clinical laboratory results Pharmacokinetic 10. Maximum and minimum serum concentration of Atezo Immunogenicity 11. Incidence of anti-therapeutic antibodies (ATAs) during the study relative to the prevalence of ATAs at baseline. |
1. Tasso di risposta obiettiva (ORR) 2. Durata della risposta (DOR) 3. PFS valutata dall’Indipendent Review Facility 4. PFS valutato dallo sperimentatore usando RECIST v1.1 (Atez monoterapia vs. placebo più chemioterapia a base di platino) 5. tasso di OS 6. tasso di PFS 7. Il tempo di peggioramento dello stato di salute globale e la funzione fisica misurata dal EORTC QLQ-C30 Sicurezza 8. L'incidenza, la natura e la gravità degli eventi avversi 9. Le variazioni di segni vitali e dei risultati clinici di laboratorio farmacocinetiche 10. massima e minima concentrazione sierica di immunogenicità atezolizumab 11. Incidenza degli anticorpi anti-terapeutici (anti-therapeutic antibody, ATA) durante lo studio in relazione alla prevalenza degli ATA al basale |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. Up to 44 months 5-6. 1 year 7-9. Up to 44 months 10-11. Pre-dose Cycle (C) 1 Day (D) 1, D1 of C2, C3, C4, and C8, at treatment discontinuation, 120 days (+/- 30 days) after last dose of Atezo. |
1-4. Fino a 44 mesi; 5-6. 1 anno;7-9. Fino a 44 mesi; 10-11. Pre-dose di ciclo (C) 1 giorno (D) 1, D1 di C2, C3, C4, C8 e, alla sospensione del trattamento, 120 giorni +/- 30 giorni) dopo l'ultima dose di atezolizumab. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 |
Immunogenicit¿ |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
¿ stato aggiunto un terzo braccio di trattamento (atezolizumab in aperto monoterapia) |
English a third treatment arm was added (open-label atezolizumab monotherapy) |
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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 | 3 |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
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 |
Australia |
Brazil |
Chile |
China |
Hong Kong |
Korea, Republic of |
Mexico |
Montenegro |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
Belgium |
Estonia |
Finland |
Greece |
Italy |
Netherlands |
Poland |
Portugal |
Romania |
Slovenia |
Spain |
United Kingdom |
Czechia |
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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
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The end of this study is defined as the date when the required number of deaths has been observed for the final analysis of OS in the global study¿s intend-to-treat population or when the required number of OS events in patients enrolled in China has occurred, whichever is later. Additionally, the Sponsor may decide to terminate the study at any time. |
La fine di questo studio ¿ definita come la data in cui ¿ stato osservato il numero di morti richiesta per l'analisi finale del OS nella popolazione programma ta per il trattamanto dallo studio globale o quando si ¿ verificato il numero di eventi OS richiesto nei pazienti arruolati in Cina , se successiva. Inoltre, lo sponsor pu¿ decidere di interrompere lo studio in qualsiasi momento. tempo. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |