E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small Cell Lung Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Non-small Cell Lung Cancer |
|
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 | 19.0 |
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 estimate the treatment effect of the combination of denosumab and
standard of care (SOC) versus SOC alone on overall survival (OS). |
|
E.2.2 | Secondary objectives of the trial |
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 expression
• To assess whether any relative benefit on objective response(OR) 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 expression
• To assess whether any relative benefit on OR 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
• To assess serum denosumab trough levels
• To assess the safety and tolerability of denosumab compared with
placebo in combination with standard of care therapy |
|
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 |
|
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) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when approximately 149 deaths occur) |
|
E.5.2 | Secondary end point(s) |
• Tumor tissue RANK expression in correlation with
o OS
o Objective response rate (complete response [CR] + partial response
[PR]) based on modified RECIST 1.1
• 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
• Objective response rate based on modified RECIST 1.1
• Clinical benefit rate ([all objective response] + [SD or better for at
least 16 weeks]) based on modified RECIST 1.1
• PFS based on modified RECIST 1.1
• Serum denosumab trough levels
• Treatment-emergent adverse events |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when approximately 149 deaths occur) |
|
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 |
Australia |
Canada |
European Union |
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
|
If denosumab is determined to have a positive benefit:risk profile,
the end of the study is defined as approximately 4 weeks after the last
dose of
denosumab in the open-label treatment phase. If the benefit:risk
profile is not positive, the end of the clinical study is defined as the last subject's last
follow-up assessment, or withdrawal from study, in the long-term
follow-up phase. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |
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 |