| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced NSCLC harbouring EGFR mutations (del19 or L858R). |
| Cancro del polmone non a piccole cellule in stadio avanzato con mutazioni (del19 o L858R) del recettore del fattore di crescita EGFR |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced lung cancer |
| cancro del polmone avanzato |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung 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 progression free survival (PFS) of patients with advanced non-squamous NSCLC |
| Determinare la sopravivenza libera da progressione (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate secondary measures of clinical efficacy. - To assess the safety and the tolerability of the erlotinib and bevacizumab combination. - To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival. - To monitor EGFR mutations (including T790M) in serum longitudinally. - To evaluate molecular biomarkers related to EGFR TKI and bevacizumab. - To determine the feasibility of re-biopsies at the time of progression and geneexpression arrays for decision-making for second-line treatment - To study the feasibility of recommending customized second-line chemotherapy based on BRCA1 and AEG-1 mRNA levels. |
| Valutare misure secondarie di efficacia clinica.Verificare la sicurezza ed efficacia della combinazione erlotinib e bevacizumab.Valutare la correlazione tra,BRCA1 mRNA,espressione di AEG-1 mRNA e T790M,e la sopravvivenza libera da progressione.Seguire l’andamento nel tempo delle mutazioni di EGFR (compreso T790M) nel siero.Valutare biomarcatori molecolari correlati a EGFR TKI e bevacizumab.Determinare la possibilita' di poter sostenere la decisione per il trattamento di seconda linea sulla base della valutazione dell’espressione genica attraverso nuove biopsie al momento delle progressione.Studiare la possibilita' di poter indicare una seconda linea di trattamento personalizzata sulla base dei livelli di mRNA di BRCA1 AEG- 1. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Age ≥ 18 years - ECOG performance status 0-2 - Adequate haematological function: haemoglobin > 9 g/dL, neutrophils count >1.5×109/L, platelet count > 100 × 109/L - Adequate coagulation: INR ≤ 1.5 - Adequate liver function: Total bilirubin < 1.5 × ULN, ALT and/or AST < 2.5 ×ULN, alkaline phosphatase < 5 ULN, except in the presence of exclusive bone metastases and in the absence of any liver disorder. - Adequate renal function: Calculated creatinine clearance ≧ 50 mL/min (Cockroft-Gault) and proteinuria < 2+ (dipstick). - Oral swallowing capability, patient capable of proper therapeutic compliance, and accessible for correct follow-up. - Life expectancy of at least 2 months. - Women of childbearing age, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning treatment. - All sexually active men and women of childbearing age must use an effective contraceptive method during the study treatment and for a period of at least 12 months following the last administration of trial drugs. - Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to any trial-related intervention for a) trial treatment b) tissue submission for central review and central EGFR testing Disease characteristics - Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer (NSCLC). - TNM version 7 stage IV disease including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease not amenable to curative treatment (including patients progressing after radiochemotherapy for stage III disease). - Measurable or evaluable disease (according to RECIST 1.1 criteria). - Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R). - Patients with asymptomatic and stable cerebral metastases |
| Eta' ≥ 18 anni - ECOG performance status 0-2 - Funzione ematologica adeguata: Hb > 9 g/dL, conta dei neutrofili >1.5×109/L, conta delle piastrine > 100 × 109/L - Adeguato stato coagulativo: INR ≤ 1.5 - Adeguata funzione epatica: bilirubina tot < 1.5 × ULN, ALT e/o AST < 2.5 ×ULN, fosfatasi alcalina< 5 ULN, ad eccezione del caso di presenza di metastasi ossee ed in assenza di qualsiasi malattia epatica. Adeguata funzionalita' renale: Clearence creatinina ≧ 50 mL/min (Cockroft-Gault) e proteinuria < 2+ (dipstick). Conservata capacita' di deglutizione, di collaborazione con la terapia e disponibilita' per il follow-up. Aspettativa di vita di almeno 2 mesi. Test di gravidanza, eseguito entro 7 giorni prima dell’inizio del trattamento, negativo per le donne in eta' fertile, comprese quelle che hanno avuto l’ultimo flusso mestruale negli ultimi 2 anni. Uso di un metodo contraccettivo efficace per tutti gli uomini sessualmente attivi e per le donne in eta' fertile per tutto il periodo di trattamento e per almeno 12 mesi dopo l’ultima somministrazione dei farmaci in studio. Consenso informato firmato e datato dal paziente e dallo sperimentatore prima di qualsiasi procedura legata allo studio (trattamento e campioni di tessuto per la revisione centralizzata). Diagnosi istopatologica di tumore polmonare a cellule non squamose o tumore non a piccole cellule (NSCLC). – Stadio IV (secondo TNM version 7), compreso M1a (versamento di natura maligna) o M1b (metastasi a distanza o malattia localmente avanzata non suscettibile di trattamento con intento curativo (compresi pazienti in progressione dopo radio-chemioterapia per malattia di stadio III). – Malattia misurabile o valutabile (secondo i criteri RECIST 1.1). –Delezione dell’exone 19 (del19) o mutazione dell’exone 21 (L858R) confermata dalla revisione centrale. Pazienti con metastasi cerebrali stabili ed asintomatiche. |
|
| E.4 | Principal exclusion criteria |
| - Patients with increased risk of bleeding, defined by: - major surgery or significant traumatic injury within 28 days prior to inclusion - minor surgery (including permanent catheter insertion) within 24 hours prior to first treatment with bevacizumab - history or evidence of bleeding diathesis or hereditary coagulopathy - history of haemoptysis (defined as at least half a teaspoon's emission of red blood) in the 3 months prior to inclusion) - evidence by CT of tumor cavitations, or tumours invading or abutting major blood vessels - uncontrolled hypertension (systolic blood pressure > 150 mm Hg and / or diastolic > 100 mm Hg) - Patients with clinically significant cardiovascular diseases, including - cerebral vascular accident (<6 months before inclusion) - acute myocardial infarction (<6 months before inclusion) - unstable angina - congestive heart failure class > NYHA II - serious cardiac arrhythmia requiring medication during the study and which could interfere with regularity of study treatment or is not controlled with medication. |
| - Pazienti con aumentato rischio emorragico definito come: -chirurgia maggiore o trauma significativo entro 28 giorni prima dell’inclusione - chirurgia minore (compreso il posizionamento di catetere a permanenza) entro 24 ore prima della prima somministrazione di bevacizumab - anamnesi positiva o evidenza clinica di diatesi emorragica o di coagulopatia ereditaria – anamnesi positiva per emottisi (definita come l’emissione di almeno ½ cucchiaino di sangue rosso) nei 3 mesi precedenti l’inclusione) - riscontro nella TAC di tumori escavati o di tumori invasivi o in prossimita' dei grandi vasi – ipertensione arteriosa non controllata (sistolica> 150 mm Hg e/o diastolica> 100 mm Hg) - Pazienti con patologia cardiovascolare clinicamente significativa compreso accidenti cerebrali vascolari (<6 mesi prima dell’inclusione) - infarto acuto del miocardio (<6 mesi prima dell’inclusione) - angina instabile - scompenso cardiaco class > NYHA II - aritmia cardiaca severa che richiede trattamento farmacologico durante lo studio che potrebbe interferire con il trattamento previsto dallo studio oppure non e' controllata da farmaci. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS is defined as the time from the date of enrolment until documented progression or death, whichever occurs first) |
| Sopravivenza libera da progressione(PFS) definita come il tempo trascorso dalla data di arruolamento allo studio fino alla documentazione di progressione o morte) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The final evaluation will be done within 6 months after the last visit of the last patient, approximately 54 months after the inclusion of the first patient. |
| La valutazione finale avra' luogo entro 6 mesi dopo l'ultima visita dell'ultimo paziente, approssimativamente dopo 54 mesi dall'inclusione del primo paziente. |
|
| E.5.2 | Secondary end point(s) |
| Overall survival (OS) - Time to treatment failure (TTF) - Objective response (OR) - Adverse events graded according to CTCAE V4.0 - Disease control (DC) - Duration of response (DR) |
| Sopravivenza globale(OS) - Tempo al fallimento del trattamento(TTF) - Risposta obiettiva (OR) - Eventi avversi (secondo CTCAE V4.0 - Controllo di malattia(DC) - Durata della risposta(DR) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final evaluation will be done within 6 months after the last visit of the last patient, approximately 54 months after the inclusion of the first patient. |
| La valutazione finale avra' luogo entro 6 mesi dopo l'ultima visita dell'ultimo paziente, approssimativamente dopo 54 mesi dall'inclusione del primo paziente. |
|
| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 50 |
| 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 | No |
| 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 |
|
| 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
|
| Patients will be followed until death – thus follow-up estimated up to 3 years following the enrolment of the last patient. The trial will end with the preparation of the final report, scheduled for month 54 after the inclusion of first patient. |
| I pazienti verranno seguiti fino alla loro morte quindi il follow-up e' stimato fino a 3 anni dopo l'arruolamento dell'ultimo paziente. Il trial finira' con la preparazione del report finale circa 54 mesi dopo l'inclusione del primo paziente. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 54 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 54 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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