E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Non-small Cell Lung Cancer |
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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 | 18.0 |
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) |
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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 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 |
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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 |
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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 |
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E.4 | Principal exclusion criteria |
• Known presence of epidermal growth factor receptor (EGFR) mutation
• Known brain metastases
• Any prior therapy (before randomization) 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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Tumor tissue RANK expression in correlation with overall survival |
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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) |
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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 |
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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) |
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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 | 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 | 5 |
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 |
Australia |
Canada |
European Union |
United States |
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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
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The time when the last subject is assessed, including for survival
assessment, or receives an intervention for evaluation in the study. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 1 |
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 |