E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Small-Cell Lung Cancer |
cancro al polmone non a piccole cellule |
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E.1.1.1 | Medical condition in easily understood language |
Lung Cancer |
cancro al polmone |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine the efficacy of onartuzumab+erlotinib compared with placebo+erlotinib, as measured by progression-free survival (PFS) assessed by the investigator. |
Determinare l'efficacia di onartuzumab erlotinib rispetto a placebo erlotinib, misurata in base alla sopravvivenza libera da progressione (PFS) secondo il giudizio dello sperimentatore. |
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E.2.2 | Secondary objectives of the trial |
- To determine the efficacy of onartuzumab+erlotinib compared with placebo+erlotinib as measured by overall survival (OS)
- To determine the efficacy of onartuzumab+erlotinib compared with placebo+erlotinib as measured by objective response rate
- To determine the impact of onartuzumab+erlotinib compared with placebo+erlotinib as measured by time to deterioration (TTD) in patient reported lung cancer symptoms
- To compare other patient-reported outcomes (PROs) following treatment with onartuzumab+erlotinib versus placebo+erlotinib as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13
- To compare the safety of onartuzumab+erlotinib versus placebo+erlotinib, including serious adverse events (SAEs)
- To evaluate the pharmacokinetics of onartuzumab
- To evaluate serum levels and incidence of anti-therapeutic antibodies (ATAs) against onartuzumab |
- Determinare l'efficacia di onartuzumab erlotinib rispetto a placebo erlotinib misurata in base al tasso di sopravvivenza globale (OS).
- Determinare l'efficacia di onartuzumab erlotinib rispetto a placebo erlotinib misurata tramite percentuale di risposta obiettiva (ORR).
- Determinare l'impatto di onartuzumab erlotinib rispetto a placebo erlotinib misurato come tempo trascorso prima del deterioramento (TTD) nei sintomi del cancro polmonare riferiti dai pazienti.
- Confrontare altri risultati riferiti dai pazienti (PRO) in seguito al trattamento con onartuzumab erlotinib rispetto a placebo erlotinib, mediante analisi basata su EORTC QLQ-C30 e EORTC QLQ-LC13.
- Confrontare la sicurezza di onartuzumab erlotinib rispetto a placebo erlotinib, compresi gli eventi avversi gravi (SAE).
- Valutare la farmacocinetica di onartuzumab.
- Valutare i livelli sierici e l'incidenza di anticorpi antiterapeutici (ATA) contro onartuzumab.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Ability and willingness to provide written informed consent and to comply with the study protocol
- Male or female, 18 years of age or older
- ECOG performance status of 0 or 1
- Histologically confirmed, unresectable Stage IIIB or IV NSCLC tumor
- No prior treatment for unresectable Stage IIIB or IV NSCLC
- MET positive status (>= 50% of tumor cells with membrane and/or cytoplasmic staining at moderate [IHC clinical score 2+] or high [3+] intensity)
- An activating EGFR mutation (exon 19 deletion or L858R, G719X, or S768I point mutation), as determined by the central laboratory on an adequate tissue sample
- Measurable radiographic evidence of disease according to RECIST v1.1
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- Capacità e volontà di fornire un consenso informato scritto e conformarsi al protocollo dello studio
- Sesso maschile o femminile ed età ≥ 18 anni
- Stato di performance ECOG 0 o 1
- Tumore NSCLC di stadio IIIB o IV non resecabile, confermato istologicamente
- Nessun precedente trattamento per NSCLC di stadio IIIB o IV non resecabile
- Stato MET-positivo (50% di cellule tumorali con colorazione della membrana e/o del citoplasma a intensità da moderata [punteggio clinico IHC 2+] o elevata [3+])
- Una mutazione attivante di EGFR (delezione dell'esone 19 o mutazione puntiforme L858R, G719X o S768I), come stabilito dal laboratorio centrale su un campione di tessuto adeguato
- Evidenza radiografica di malattia in base ai criteri RECIST v1.1 |
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E.4 | Principal exclusion criteria |
- Prior treatment for unresectable Stage IIIB or IV NSCLC
- Patients who have received adjuvant or neoadjuvant therapy for non-metastatic disease in which relapse occurred > 12 months after final treatment are eligible.
- Patients may have received prior radiation therapy provided they have recovered from any toxic effects thereof and that at least 7 days have elapsed between the last fraction and randomization.
-Prior exposure to agents targeting either the HGF or MET pathway, including but not limited to crizotinib, cabozantinib, ficlatuzumab, rilotumumab, and tivantinib.
- Exposure to an investigational or marketed agent that can act by EGFR inhibition.
- Pleural effusion, pericardial fluid, or ascites requiring drainage every other week or more frequently.
-Exon 20 insertion or the T790M point mutation in EGFR (which are activating but confer resistance to erlotinib), as determined by the central laboratory on an adequate tissue sample.
- Brain metastasis or spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated central nervous system (CNS) metastases or spinal cord compression without evidence of clinically stable disease for ≥ 14 days.
-History of another malignancy in the previous 5 years, unless cured by surgery alone and continuously disease free.
- Radiographically evident interstitial lung disease (ILD; as evidenced by one or more of the following manifestations: interstitial pneumonia, pneumonitis, radiation pneumonitis, organizing pneumonia, pulmonary fibrosis, acute respiratory distress syndrome, lung infiltration, or alveolitis), concurrent infection, or a history of any of these conditions.
- Abnormal haematologic, biochemical or organ function tests.
- Significant medical co-morbidities.
- Pregnancy or the lack of use of appropriate contraception.
- Life expectancy <12 weeks. |
- Trattamento precedente per NSCLC di stadio IIIB o IV non resecabile
- I pazienti che hanno ricevuto una terapia adiuvante o neoadiuvante per patologia non metastatica e nei quali si è manifestata una recidiva 12 mesi dopo il trattamento finale sono eleggibili.
- I pazienti possono aver ricevuto una radioterapia precedente a condizione che si siano ripresi da eventuali effetti tossici della stessa e siano trascorsi almeno 7 giorni tra l'ultima frazione e la randomizzazione.
- Precedente esposizione ad agenti mirati al pathway HGF o MET, inclusi ma non si limitano a crizotinib, cabozantinib, ficlatuzumab, rilotumumab e tivantinib
- Esposizione a un agente sperimentale o in commercio in grado di agire tramite inibizione di EGFR.
Effusione pleurica, liquido peri-cardiaco o asciti che richiedono drenaggio ogni due settimane o con maggiore frequenza.
-Mutazione di inserzione dell'esone 20 o mutazione puntiforme T790M in EGFR (che determinano attivazione ma anche resistenza a erlotinib) come stabilito dal laboratorio centrale su un campione di tessuto adeguato.
- Metastasi al cervello o compressione del midollo spinale non trattate in maniera definitiva chirurgicamente e/o con radiazioni o metastasi al sistema nervoso centrale (SNC) precedentemente diagnosticate e trattate o compressione del midollo spinale senza evidenza di malattia stabile per 14 giorni.
- Anamnesi di un’altra malattia maligna nei 5 anni precedenti, a meno che non sia stata curata solo chirurgicamente e il paziente non ne mostri traccia in via continuativa.
- Malattia polmonare interstiziale evidenziata radiograficamente (ILD; dimostrata da una o più delle seguenti manifestazioni: polmonite interstiziale, polmonite, polmonite da radiazioni, polmonite organizzativa, fibrosi polmonare, sindrome da distress respiratorio acuto, infiltrazione polmonare o alveolite), infezione concomitante o storia di una qualsiasi di queste condizioni.
- Anomalie nei test ematologici, biochimici e di funzionalità d’organo.
- Significanti co-morbidità
- Gravidanza o mancanza di utilizzo di un metodo anticoncezionale appropriato.
- Aspettativa di vita inferiore alle 12 settimane. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- PFS, defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator using RECIST v1.1) or death, whichever occurs first |
PFS, definita come il tempo intercorso tra la randomizzazione e la prima manifestazione di progressione della malattia (come stabilito dallo sperimentatore in base ai criteri RECIST v1.1) o il decesso, a seconda dell'evento che si verifica per primo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is defined as the time from randomization to disease-progression or death by any cause |
La PFS è definita come il tempo dalla randomizzazione alla progressione di malattia o alla morte per qualsiasi causa. |
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E.5.2 | Secondary end point(s) |
Overall Survival, ORR, PROs, PK and Safety |
Overall Survival, ORR, PROs, PK and Safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis for all endpoints except OS, which will be assessed after 172 OS events, or approximately 53 months after the first patient is enrolled. |
analisi finali per tutti gli end-points a parte l’OS che sarà valutata dopo 172 eventi di OS, o approssimativamente 53 mesi dopo l’arruolamento del primo 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 | 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 |
Tolerability, QoL, Serum levels and incidence of anti-therapeutic
antibodies (ATAs) against Onartuzumab |
Tollerabilità, Qualità della vita, livelli serici degli anticorpi anti-terapeutici (ATA) contro onartuzumab. |
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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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
China |
France |
Germany |
Hong Kong |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Philippines |
Poland |
Singapore |
Spain |
Taiwan |
Thailand |
United States |
Vietnam |
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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 primary efficacy analysis will occur when 174 investigator-assessed PFS events in the ITT population have occurred. Survival follow-up will continue until 172 OS events have occurred; this is expected to be 53 months after the first patient enrolled, assuming the median OS in the control group is 22 months and the OS HR=0.65. Patients may be allowed to continue treatment, if no experienced disease progression and have not experienced intolerable toxicity, with continued safety follow up. |
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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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |