E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Stage IIIBIV) |
carcinoma polmonare non a piccole cellule localmente avanzato, o metastatico (stadio IIIB-IV) |
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E.1.1.1 | Medical condition in easily understood language |
Non-Small Cell Lung Cancer |
carcinoma polmonare non a piccole cellule |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029514 |
E.1.2 | Term | Non-small cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066490 |
E.1.2 | Term | Progression of non-small cell lung cancer |
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 |
Sub-study A (PD-L1-positive population) To assess the efficacy of MEDI4736 monotherapy compared with Standard of Care in terms of OS and PFS Sub-study B (PD-L1-negative population) To assess the efficacy of MEDI4736+tremelimumab treatment compared with Standard of Care in terms of OS and PFS
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Sottostudio A (popolazione positiva al PD-L1) Valutare l’efficacia del trattamento con MEDI4736 in monoterapia rispetto allo standard di cura in termini di OS e PFS Sottostudio B (popolazione negativa al PD-L1) Valutare l’efficacia del trattamento con MEDI4736+tremelimumab rispetto allo standard di cura in termini di OS e PFS
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E.2.2 | Secondary objectives of the trial |
For both sub-studies A and B: - To assess the efficacy in terms of: Proportion of patients alive at 12 months from randomisation (OS12), Objective response rate (ORR), Duration of response (DoR),Proportion of patients alive and progression free at 6 months (APF6) and 12 months (APF12) from randomisation and time from randomisation to second progression (PFS2) - To assess the safety and tolerability profile - To assess the PK of MEDI4736 and tremelimumab - To investigate the immunogenicity of MEDI4736 and tremelimumab - To assess symptoms and health-related QoL In additon for Sub-study B: - To evaluate the efficacy of MEDI4736 + tremelimumab treatment compared with a) MEDI4736 monotherapy and b) tremelimunab monotherapy |
Per entrambe i sottostudi A e B: - Valutare ulteriormente l’efficacia in termini di: percentuale di pazienti vivi a 12 mesi dalla randomizzazione (OS12), il tasso di risposta obiettiva (ORR), la durata della risposta (DoR), la percentuale di pazienti vivi e senza progressione a 6 mesi (APF6) e 12 mesi (APF12) dalla randomizzazione e il tempo dalla randomizzazione alla seconda progressione (PFS2) - Valutare il profilo di sicurezza e tollerabilità - Valutare la PK di MEDI4736 e tremelimumab - Studiare l’immunogenicità di MEDI4736 e tremelimumab - Valutare i sintomi e la QoL correlata alla salute Inoltre, per il Sottostudio B: - Valutare l’efficacia del trattamento con MEDI4736+tremelimumab rispetto ad a) MEDI4736 in monoterapia e b) tremelimumab in monoterapia |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies Specify title, date and version of each substudy with relative objectives: 1) Sub-study A (patients with PD-L1-positive tumours) compares: • MEDI4736 (10 mg/kg once every 2 weeks [Q2W] intravenously [iv] for up to 12 months) (150 patients) • Standard of Care (restricted to erlotinib, gemcitabine or vinorelbine) (150 patients). ¿ Erlotinib: 150 mg once daily, orally ¿ Gemcitabine: 1000 mg/m2 iv on Days 1, 8, and 15 of a 28-day cycle ¿ Vinorelbine: 30 mg/m2 iv on Days 1, 8, 15 and 22 of a 28-day cycle. 2) Sub-study B (patients with PD-L1-negative tumours): • MEDI4736 + Tremelimumab (MEDI4736 20 mg/kg plus Tremelimumab 1 mg/kg once every 4 weeks [Q4W] iv for up to 12 weeks [4 doses]), then MEDI4736 alone (10 mg/kg Q2W iv, starting at Week 16, for 34 weeks [18 doses]) (225 patients) • Standard of Care (see under Sub-study A, 150 patients) • MEDI4736 (10 mg/kg Q2W iv for up to 12 months) (150 patients) • Tremelimumab (10 mg/kg Q4W iv for 24 weeks then Q12W for 24 weeks) (75 patients). 3) Pharmacogenetics Research substudy
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Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: 1) Sottostudio A (pazienti con tumori positivi al PD-L1): • MEDI4736 (10 mg/kg una volta ogni 2 settimane [once every 2 weeks, Q2W] per via endovenosa [e.v.], per massimo 12 mesi) (150 pazienti) • Standard di cura (limitato a erlotinib, gemcitabina o vinorelbina) (150 pazienti). ¿ Erlotinib: 150 mg una volta al giorno, per via orale ¿ Gemcitabina: 1000 mg/m2 e.v. ai Giorni 1, 8 e 15 di un ciclo di 28 giorni ¿ Vinorelbina: 30 mg/m2 e.v. ai Giorni 1, 8, 15 e 22 di un ciclo di 28 giorni. 2) Sottostudio B (pazienti con tumori negativi al PD-L1): • MEDI4736 + Tremelimumab (MEDI4736 20 mg/kg più Tremelimumab 1 mg/kg una volta ogni 4 settimane [Q4W] iv fino a un massimo di 12 settimane [4 dosi]), poi MEDI4736 da solo (10 mg/kg Q2W, iniziando alla Settimana 16, per 34 settimane [18 dosi] (225 pazienti) Standard di cura (si veda Sottostudio A, 150 pazienti) • MEDI4736 (10 mg/kg Q2W e.v. per massimo 12 mesi) (150 pazienti) • Tremelimumab (10 mg/kg Q4W e.v. per 24 settimane e, a seguire, Q12W per 24 settimane) (75 pazienti). 3) Sottostudio di ricerca farmacogenetica
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E.3 | Principal inclusion criteria |
- Aged at least 18 years - Documented evidence of NSCLC (Stage IIIB/ IV disease) - Disease progression or recurrence after both a platinum-based chemotherapy regimen and at least 1 additional regimen for treatment of NSCLC - World Health Organization (WHO) Performance Status of 0 or 1 - Estimated life expectancy = 12 weeks |
- Pazienti di età pari o superiore ai 18 anni - I pazienti devono avere un NSCLC documentato (malattia di stadio IIIB/IV) - Progressione o recidiva di malattina dopo un trattamento chemioterapico a base di platino e di almeno 1 ulteriore terapia sistemica per il trattamento del NSCLC - Performance Status di 0 o 1 secondo Organizzazione Mondiale della Sanità (OMS) - Aspettativa di vita stimata = 12 settimane |
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E.4 | Principal exclusion criteria |
- Prior exposure to any anti-PD-1 or anti-PD-L1 antibody - Brain metastases or spinal cord compression unless asymptomatic, treated and stable (not requiring steroids) - Active or prior documented autoimmune disease within the past 2 years - Evidence of severe or uncontrolled systemic disease, including active bleeding diatheses or active infections including acute or chronic hepatitis B, C and HIV - Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy - Known EGFR TK activating mutations or ALK rearrangements. Patients with EGFR TK inactivating mutations eg, exon 20, are eligible. - Any prior Grade =3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1 - Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis) |
- Precedente esposizione a qualsiasi anticorpo anti-PD-L1 o anti-PD-1; - metastasi cerebrali o compressione del midollo spinale salvo ove asintomatiche, trattate e stabili (che non richiede steroidi) - Malattia autoimmune attiva o pregressa documentata nei due anni precedenti - Evidenza di una malattia sistemica grave o non controllata, compresa diatesi emorragica o infezioni attive, incluse epatite B, C e HIV acuta o cronica - Qualsiasi tossicità irrisolta CTCAE> Grado 2 dalla precedente terapia anti-tumorale - Mutazioni attivanti TK EGFR note o riarrangiamenti ALK.I pazienti con mutazioni inattivanti della tirosin chinasi EGFR, ossia esone 20, sono idonei. - Qualsiasi precedente evento avverso di grado =3 immunocorrelato (irAE) durante la ricezione di qualsiasi agente immunoterapico precedente, o qualsiasi Irae> Grado 1 irrisolto - Malattia intestinale infiammatoria attiva o pregressa documentata (ad es., morbo di Crohn, colite ulcerosa) |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Overall survival (OS) - Progression free survival (PFS) |
- Sopravvivenza globale (OS) - Sopravvivenza senza progressione (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- OS: up to 3 years after first patient randomized - PFS: up to 3 years after first patient randomized |
- OS: fino a 3 anni dopo la randomizzazione del primo paziente - PFS: fino a 3 anni dopo la randomizzazione del primo paziente
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E.5.2 | Secondary end point(s) |
- Proportion of patients alive at 12 months from randomisation (OS12) - Objective response rate (ORR) - durata della risposta (DoR) |
- Percentuale di pazienti vivi a 12 mesi dalla randomizzazione (OS12) - tasso di risposta obiettiva (ORR) - Duration of response (DoR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS12: up to 1 year after last patient randomized - ORR: up to 3 years after the first patient randomized - DoR: up to 3 years after the last patient randomized |
- OS12: fino a 1 anno dopo la randomizzazione dell'ultimo paziente - ORR: fino a 3 anni dopo la randomizzazione del primo paziente - DoR: fino a 3 anni dopo la randomizzazione dell'ultimo paziente |
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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 | Yes |
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 | Yes |
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 of MEDI4736 monotherapy and MEDI4736 + tremelimumab symptoms and health-related QoL |
Immunogenicità di MEDI4736 in monoterapia e MEDI4736 + tremelimumab sintomi e qualità della vita correlata alla salute |
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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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
assegnazione al sottostudio A e sottostudio B in base allo stato dell'espressione di PD L1 tumorale |
assignment to Substudy A and Substudy B respctively based on PDL1 tumor expression status |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 92 |
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 |
Argentina |
Australia |
Canada |
Chile |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Philippines |
Russian Federation |
Serbia |
Singapore |
South Africa |
Taiwan |
Thailand |
Turkey |
United States |
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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 study will continue until the last patient completes 90 days of follow-up after re-treatment or the last patient discontinues for any reason from the progression-free follow-up (so no further patients are eligible for re-treatment). |
Lo studio continuerà fino a quando l’ultimo paziente avrà completato i 90 giorni di follow-up dopo il ritrattamento o fino a quando l’ultimo paziente sarà discontinuato per qualsiasi ragione dalla progression-free follow-up (quindi non ci saranno ulteriori pazienti eligibili per il ritrattamento). |
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |