E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Biliary tract cancer |
Tumore delle vie biliari |
|
E.1.1.1 | Medical condition in easily understood language |
Biliary tract cancer is a rare type of cancer that occurs in a bile duct. Patients with advanced biliary tract cancer generally have a poor prognosis. |
Il cancro del tratto biliare è un raro tipo di cancro che si verifica in un dotto biliare. I pazienti con carcinoma avanzato delle vie biliari hanno generalmente una prognosi sfavorevole. |
|
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 | 10008593 |
E.1.2 | Term | Cholangiocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10001141 |
E.1.2 | Term | Adenocarcinoma |
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 (Atezo)+ bevacizumab (Bev)+ cisplatin and gemcitabine (CisGem) compared with Atezo+ placebo (PBO)+CisGem based on progression free survival |
•Valutare l’efficacia di Atezo+Bev+CisGem rispetto ad Atezo+PBO+CisGem basato sulla sopravvivenza libera da progressione |
|
E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of Atezo+Bev+CisGem compared with Atezo+PBO+CisGem based on overall survival, confirmed objective response rate, duration of response, disease control rate, time to confirmed deterioration
•To evaluate the safety of Atezo+Bev+CisGem compared with Atezo+PBO+CisGem
•To characterize the pharmacokinetics of atezolizumab when given in combination with bevacizumab and/or gemcitabine/cisplatin
•To evaluate the immune response to atezolizumab
|
• Valutare l’efficacia di Atezo+Bev+CisGem rispetto ad Atezo+PBO+CisGem basato sulla sopravvivenza globale, tasso di risposta obiettiva confermato, durata della risposta, tasso di controllo della malattia, tempo al peggioramento confermato. •Valutare la sicurezza di Atezo+Bev+CisGem rispetto ad Atezo+PBO+CisGem •Caratterizzare la farmacocinetica di atezolizumab somministrato in associazione a bevacizumab e/o gemcitabina/cisplatino •Valutare la risposta immunitaria ad atezolizumab |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Age >= 18 years at the time of signing Informed Consent Form •Ability to comply with the study protocol •Considered to be eligible to receive platinum-based chemotherapy, in the investigator’s judgment •Documentation of recurrent/metastatic or locally advanced unresectable disease based on computed tomography (CT) or magnetic resonance imaging (MRI) scans •Histologically or cytologically confirmed diagnosis of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer •No prior systemic therapy (including systemic investigational agents) for advanced biliary tract cancer •At least one measurable untreated lesion (per RECIST v1.1) •Adequate biliary drainage with no evidence of ongoing infection •Availability of a representative tumor specimen that is suitable for determination of PD-L1 status via central testing •Negative HIV test at screening with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4° count >= 200/mcL, and have an undetectable viral load •Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (HCV) tests •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 •Life expectancy of > 3 months •Adequate hematologic and end-organ function •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs while they are receiving atezolizumab and bevacizumab and for 5 months after the final dose of atezolizumab and for 6 months after the final dose of bevacizumab, cisplatin or gemcitabine, whichever is later •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm during the treatment period and for 6 months after the final dose of bevacizumab, cisplatin or gemcitabine, whichever is later, to avoid exposing the embryo |
•Età >= 18 anni al momento della sottoscrizione del modulo di consenso informato •Capacità di rispettare il protocollo dello studio •Idoneità al trattamento con una chemioterapia a base di platino secondo il parere dello sperimentatore. •Documentazione di malattia recidivante/metastatica o localmente avanzata non resecabile in base ai referti della tomografia computerizzata (TC) o della risonanza magnetica (RM). •Diagnosi di iCCA, eCCA o GBC confermata dall’esame istologico o citologico •Nessuna precedente terapia sistemica (compresi agenti sperimentali sistemici) per BTC avanzato. •Almeno una lesione non trattata misurabile (secondo i criteri RECIST v1.1). •Drenaggio biliare adeguato senza evidenze di infezione in corso •Disponibilità di un campione tumorale rappresentativo adatto per la determinazione dello stato di PD-L1 tramite analisi centrale •Test negativo per il virus dell’immunodeficienza umana (HIV) allo screening con la seguente eccezione: i pazienti positivi al test dell’HIV allo screening saranno ritenuti idonei purché siano sottoposti a terapia retrovirale stabile e presentino una conta di linfociti CD4°200/mcl e una carica virale non rilevabile. •Stato virologico documentato di epatite confermato dai test di screening per il virus dell’epatite B (HBV) e C (HCV). •Performance status secondo l’ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1 •Aspettativa di vita >3 mesi •Adeguata funzionalità ematologica, epatica e renale •Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o a far uso di metodi contraccettivi e consenso ad astenersi dalla donazione degli ovuli durante il trattamento con atezolizumab e bevacizumab per 5 mesi dopo l’ultima dose di atezolizumab e per 6 mesi dopo l’ultima dose di bevacizumab cisplatino o gemcitabina, a seconda del farmaco somministrato per ultimo •Per gli uomini: consenso a praticare l’astinenza dai rapporti eterosessuali o a usare il preservativo e consenso ad astenersi dalla donazione del seme durante il periodo di trattamento e per 6 mesi dopo l’ultima dose di bevacizumab, cisplatino o gemcitabina |
|
E.4 | Principal exclusion criteria |
•Recurrent disease =<6 months after curative surgery or =<6 months after the completion of therapy •Prior local regional therapy •Combined or mixed hepatocellular/cholangiocarcinoma •Clinically sign. hepatic encephalopathy within 12 months prior to D1 of C1 •NCI CTCAE Grade >=2 peripheral neuropathy •Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to D1 C1 •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 on screening chest CTscan •Sign. cardiovascular disease within 3 months prior to D1 C1, unstable arrhythmia, or unstable angina •History of malignancy other than BTC within 5 years prior to screening •Active tuberculosis •Severe infection within 4 weeks prior to D1 C1 •Treatment with oral or IV antibiotics within 2 weeks prior to D1 C1 •Prior allogeneic stem cell or solid organ transplantation •Waiting list for liver transplantation •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug •Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezo or within 6 months after the final dose of beva, cisplatin or gemcitabine •Co-infection with HBV and HCV •Uncontrolled or symptomatic hypercalcemia •History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins •History of allergic reactions to cisplatin or other platinum-containing compounds •Known hypersensitivity to gemcitabine •Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezo or beva formulations •Treatment with a live, attenuated vaccine within 4 weeks prior to D1 C1 or anticipation of need for such a vaccine during atezo treatment or within 5 months after the final dose of atezo •Treatment with investigational therapy within 4 weeks prior to D1 C1 •Prior treatment with CD137 agonists or immune checkpoint blockade therapies •Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to D1 C1 •Treatment with systemic immunosuppressive medication within 2 weeks prior to D1 C1 or anticipation of need for systemic immunosuppressive medication during study treatment •Inadequately controlled arterial hypertension (defined as systolic BP > 150 mmHg and/or diastolic BP > 100 mmHg), based on an average of at least three BP readings at two or more sessions •History of hypertensive crisis or hypertensive encephalopathy •Significant vascular disease within 6 months prior to D1 C1 •History of hemoptysis within 1 month prior to D1 C1 •Evidence of bleeding diathesis or significant coagulopathy •Current or recent use of aspirin ( > 325 mg/day)or current or recent treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol •Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose •Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to D1 C1 •History of abdominal or tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to D1 C1 •Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure •Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture •Major surgical procedure within 4 weeks prior to D1 C1 or anticipation of need for a major surgical procedure during the study •History of clinically significant and uncontrolled intra-abdominal inflammatory disease within 6 months prior to D1 C1 •Chronic daily treatment with a non-steroidal anti-inflammatory drug •Preexisting renal impairment, myelosuppression, or hearing impairment |
•Malattia recidivante <=6 mesi dopo intervento chirurgico curativo o <=6 mesi dopo compl. terapia •Prec. terapia locoregionale •Carcinoma combinato o misto epato-colangiocellulare •Encefalopatia epatica clinicamente sign. 12 mesi prec. G1 C1 •Neuropatia periferica di grado >=2 •Evento pregresso di sanguinamento dovuto a varici esofagee e/o gastriche non trattate o trattate in modo incompleto 6 mesi prec. G1 C1 •Malattia autoimmune o immunodeficienza attiva o pregressa •Anamnesi pos. per fibrosi polmonare idiopatica, polmonite in org., polmonite indotta da farmaci o polmonite idiopatica, oppure evidenza di polmonite attiva alla TC del torace allo screening •Cardiovasculopatia sign. 3 mesi prec. G1 C1, aritmia o angina instabile •Anamnesi pos. per neoplasia maligna diversa dal BTC 5 anni prec. lo screening •Tubercolosi attiva •Infezione severa 4 settimane prec. G1 C1 •Trattamento con antibiotici orali o IV 2 settimane prec. G1 C1 •Prec. trapianto di cellule staminali o di organi solidi •In lista per trapianto di fegato •Qualsiasi altra malattia, disfunzione metabolica, obiettività o referto di lab. che rappresenti una controindicazione all’uso di un farmaco sperimentale •Gravidanza o allattamento o intenzione di iniziare una gravidanza durante lo studio o nei 5 mesi successivi l’ultima dose di atezo o nei 6 mesi successivi l’ultima dose di beva, cisplatino o gemcitabina •Co-infezione da HBV e HCV •Ipercalcemia •Anamnesi pos. per reazioni allergiche anafilattiche severe agli anticorpi chimerici o umanizzati o alle proteine di fusione •Anamnesi pos. per reazioni allergiche a cisplatino o ad altri composti contenenti platino •Ipersensibilità nota a gemcitabina •Ipersensibilità nota ai prodotti contenenti cellule ovariche di criceto cinese o a qualsiasi componente delle formulazioni di atezo o beva •Trattamento con vaccino vivo 4 settimane prec.i G1 C1 o necessità prevista di somministrare vaccino di questo tipo durante il trattamento con atezo o nei 5 mesi dopo l’ultima dose di atezo •Trattamento con una terapia sperimentale 4 settimane prec. G1 C1 •Prec. trattamento con agonisti di CD137 o terapie che bloccano i checkpoint immunitari •Trattamento con immunostimolanti sistemici nelle 4 settimane o nelle 5 emivite di eliminazione del farmaco prec. G1 C1 •Trattamento con immunosoppressori sistemici nelle 2 settimane prec. G1 C1 o necessità prevista di immunosoppressori sistemici durante il trattamento •Ipertensione arteriosa non adeguatamente controllata (intesa come PA sistolica >150 mmHg e/o PA diastolica >100 mmHg) •Anamnesi pos. per crisi o encefalopatia ipertensiva •Vasculopatia sign. 6 mesi precedenti G1 C1 •Anamnesi pos. per emottisi nel mese precedente G1 C1 •Evidenza di diatesi emorragica o coagulopatia sign. •Uso corrente o recente di aspirina (>325 mg/die) o trattamento corrente o recente con dipiridamolo, ticlopidina, clopidogrel e cilostazolo. •Uso corrente o recente di anticoagulanti o agenti trombolitici orali o parenterali a dose piena per finalità terapeutiche •Biopsia con ago a scatto o altra procedura chirurgica minore, escluso l’inserimento di un dispositivo di accesso vascolare 3 giorni prec. G1 C1. •Anamnesi pos. per fistola addominale o tracheoesofagea, perforazione gastrointestinale o ascesso intraddominale 6 mesi prec. G1 C1. •Evidenza di aria libera a livello addominale non spiegata da paracentesi o da una recente procedura chirurgica. •Ferita grave, ulcera attiva o frattura ossea non trattata. •Procedura di chirurgia maggiore 4 settimane precedenti G1 C1 o necessità prevista di una procedura di chirurgia maggiore durante lo studio •Anamnesi pos. per malattia infiammatoria intraddominale clinicamente sign. e non controllata 6 mesi precedenti G1 C1 •Trattamento giornaliero cronico con un farmaco antinfiammatorio non steroideo •Compromissione renale, mielosoppressione o compromissione dell’udito preesistente |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression free survival |
Sopravvivenza libera da progressione |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 5 years |
Fino a 5 anni |
|
E.5.2 | Secondary end point(s) |
1. Overall survival 2. Confirmed objective response rate as determined by the investigator according to RECIST v1.1 3. Duration of response as determined by the investigator according to RECIST v1.1 4. Disease control rate as determined by the investigator according to RECIST v1.1 5. Time to confirmed deterioration 6. Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0 7. Change from baseline in targeted vital signs 8. Change from baseline in targeted clinical laboratory test results 9. Serum concentration of atezolizumab at specified timepoints 10. Prevalence of ADAs to atezolizumab at baseline and incidence of ADAs to atezolizumab during the study |
1. Sopravvivenza globale OS 2. ORR confermato secondo quanto stabilito dallo sperimentatore in funzione dei criteri RECIST v1.1. 3. DOR secondo quanto stabilito dallo sperimentatore in funzione dei criteri RECIST v1.1 4. DCR secondo quanto stabilito dallo sperimentatore in funzione dei criteri RECIST v1.1 5. TTCD 6. Incidenza e severità degli eventi avversi, con severità stabilita in funzione dei criteri NCI CTCAE v5.0. 7. Variazione dei segni vitali di interesse rispetto al basale. 8. Variazione dei risultati degli esami clinici di laboratorio di interesse rispetto al basale. 9. Concentrazione sierica di atezolizumab a specifici timepoint. 10. Prevalenza di ADA diretti contro atezolizumab al basale e incidenza di ADA diretti contro atezolizumab durante lo studio. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-6. Up to 5 years
7-8. Baseline (Day -28 to -1) to 5 years
9-10. Day 1 of Cycle 1, 2, 3, 4, 8, 12, and 16, at treatment discontinuation visit
|
1-6. Fino a 5 anni 7-8. Basale (giorni da -28 a -1) a 5 anni 9-10. Giorno 1 del ciclo 1, 2, 3, 4, 8, 12 e 16, alla visita di interruzione del trattamento |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient reported outcomes |
Risultati riportati dal paziente |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Canada |
China |
Hong Kong |
Korea, Republic of |
Russian Federation |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
France |
Italy |
Poland |
Spain |
United Kingdom |
|
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 end of this study is defined as the date at which the last data required for study analysis are collected. |
La fine di questo studio è definita come la data in cui vengono raccolti gli ultimi dati richiesti per l'analisi dello studio. |
|
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 |