E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small Cell Lung Cancer |
Carcinoma polmonare non a piccole cellule |
|
E.1.1.1 | Medical condition in easily understood language |
Non-small Cell Lung Cancer |
Carcinoma polmonare non a piccole cellule |
|
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 | 16.0 |
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) |
|
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 assess whether any relative benefit on overall survival (OS) from the combination of denosumab and standard of care (SOC) versus SOC alone in non-small cell lung cancer (NSCLC) is associated with tumor RANK expression |
Valutare se eventuali benefici relativi sulla sopravvivenza globale (OS) dati dalla
combinazione denosumab + standard di cura rispetto al solo standard di cura nel trattamento del NSCLC sono
associati all’espressione tumorale del RANK |
|
E.2.2 | Secondary objectives of the trial |
•To assess whether any relative benefit on objective response from the combination of denosumab and SOC versus SOC alone in NSCLC is associated with tumor RANK expression
•To assess whether any relative benefit on OS from the combination of denosumab and SOC versus SOC alone in NSCLC is associated with tumor RANK ligand (RANKL) expression
•To assess whether any relative benefit on objective response from the combination of denosumab and SOC versus SOC alone in NSCLC is associated with tumor RANKL expression
•To estimate the treatment effect of the combination of denosumab and SOC versus SOC alone on:
o Objective response rate
o Clinical benefit rate
o Progression-free survival (PFS)
o OS
•To assess serum denosumab trough levels
•To assess the safety and tolerability of denosumab compared with placebo in combination with standard of care therapy |
Valutare se eventuali benefici relativi sulla risposta obiettiva dati dalla combinazione denosumab +
standard di cura rispetto al solo standard sono associati
all’espressione tumorale del RANK
• Valutare se eventuali benefici relativi sull’OS dati dalla combinazione denosumab + standard di cura
rispetto al solo standard sono associati all’espressione tumorale
del RANK ligando (RANKL)
• Valutare se eventuali benefici relativi sulla risposta obiettiva dati dalla combinazione denosumab +
standard di cura rispetto al solo standard sono associati all’espressione tumorale del RANKL
• Stimare l’effetto del trattamento della combinazione denosumab + standard di cura rispetto al solo
standard di cura su:
o Tasso di risposta obiettiva
o Tasso di beneficio clinico
o Sopravvivenza libera da progressione (PFS)
o OS
• Valutare i livelli sierici minimi di denosumab
• Valutare la sicurezza e la tollerabilità di denosumab rispetto al placebo in combinazione allo standard
di cura |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Adult subjects with histologically or cytologically confirmed stage IV NSCLC who provide a tumor sample and are planned to receive 4-6 cycles of platinum-doublet based chemotherapy
• Radiographically evaluable disease according to modified RECIST 1.1 criteria |
- soggetti adulti con NSCL di livello IV confermato istologicamente e citologicamente che hanno fornito un campione tumorale e devono ricevere 4-6 cicli di chemioterapia a base di platino
- patologie valutabili radiograficamente in accordo ai criteri RECIST 1.1 |
|
E.4 | Principal exclusion criteria |
• Known presence of epidermal growth factor receptor (EGFR) mutation
• Known brain metastases
• Prior therapy for the treatment of NSCLC, except if for non-metastatic disease and was completed at least 6 months prior to randomization
• Planned to receive bevacizumab
• Subjects with sarcomatoid, carcinoid, and mesenchymal histologies
• More than 1 year of cumulative oral bisphosphonate usage prior to randomization
• More than 1 previous dose of IV bisphosphonate administration prior to randomization
• Significant dental/oral disease, including prior history or current
evidence of osteonecrosis/ osteomyelitis of the jaw
• Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium, or vitamin D) |
- presenza conclamata di mutazione al recettore per il fattore di crescita epidermico (EGFR)
- conosciute metastasi al cervello
- precedente chemioterapia per il trattamento di NSCLC, ad eccezione se indirizzata contro patologie non metastatiche e completata almeno 6 mesi prima della randomizzazione
- previsione di ricevere bevacizumab
- soggetti con istologia sarcomatoide, carcinoma e mesenchimale |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Tumor tissue RANK expression in correlation with overall survival |
Espressione del RANK nei tessuti tumorali in correlazione con l’OS |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when a minimum of 149 deaths occur) |
la data di cut off dell'analisi primaria è event driven (esempio quando si riscontrano un minimo di 149 decessi) |
|
E.5.2 | Secondary end point(s) |
• Tumor tissue RANK expression in correlation with objective response rate (complete response [CR] + partial response [PR]) based on modified RECIST 1.1 (Appendix E of the protocol)
• Tumor tissue RANKL expression in correlation with
o OS
o Objective response rate (complete response [CR] + partial response [PR]) based on modified RECIST 1.1 (Appendix E of the protocol)
• Objective response rate based on modified RECIST 1.1
• Clinical benefit rate ([all objective response] + [stable disease or better for at least 16 weeks]) based on modified RECIST 1.1
• PFS based on modified RECIST 1.1
• OS
• Serum denosumab trough levels
• Treatment-emergent adverse events |
Espressione del RANK nei tessuti tumorali in correlazione con il tasso di risposta obiettiva (risposta
completa [CR] + risposta parziale [PR]) in base ai criteri RECIST modificati 1.1 (Appendice E)
• Espressione del RANKL nei tessuti tumorali in correlazione con
o OS
o Tasso di risposta obiettiva (risposta completa [CR] + risposta parziale [PR]) in base ai criteri
RECIST modificati 1.1 (Appendice E)
• Tasso di risposta obiettiva in base ai criteri RECIST modificati 1.1
• Tasso di beneficio clinico ([tutte le riposte obiettive] + [malattia stabile o risposta migliore per almeno
16 settimane]) in base ai criteri RECIST modificati 1.1
• PFS in base ai criteri RECIST modificati 1.1
• OS
• Livelli sierici minimi di denosumab
• Eventi avversi insorti durante il trattamento |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when a minimum of 149 deaths occur) |
la data di cut off dell'analisi primaria è event driven (esempio quando si riscontrano un minimo di 149 decessi) |
|
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 | Yes |
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 | 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) | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
European Union |
Australia |
Canada |
United States |
|
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 time when the last subject is assessed, including for survival
assessment, or receives an intervention for evaluation in the study. |
Quando l'ultimo soggetto viene valutato, inclusa la valutazione di sopravvivenza, o riceve un intervento per la valutazione. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |