E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of bone metastases in subjects with advanced cancer (excluding breast and prostate cancer) or multiple myeloma |
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MedDRA Classification |
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 if denosumab is non-inferior to zoledronic acid (Zometa) with respect to the first on-study occurrence of a skeletal related event (SRE) in subjects with advanced cancer and bone metastases (or lytic bone lesions from multiple myeloma). SRE is defined as pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. |
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E.2.2 | Secondary objectives of the trial |
-To determine if denosumab is superior to zoledronic acid with respect to the first on-study SRE -To determine if denosumab is superior to zoledronic acid with respect to the first-and-subsequent on-study SRE (multiple event analysis) -To assess the safety and tolerability of denosumab compared with zoledronic acid |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
-Adult with histologically or cytologically confirmed advanced cancers including solid tumors, multiple myeloma, and lymphoma -Current or prior radiographic (ie, x-ray, computer tomography [CT], or magnetic resonance imaging [MRI]) evidence of at least 1 bone metastasis (or lytic bone lesion from multiple myeloma) -Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 -Adequate organ function as defined by the following criteria: a) serum aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) b) serum alanine aminotransferase (ALT) ≤ 5 x ULN c) serum total bilirubin ≤ 2 x ULN d) creatinine clearance (Cockroft-Gault, formula included in Section 6.3 of protocol) ≥ 30 mL/min e) albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL). Albumin-adjusted serum calcium, if applicable, will be calculated by the central laboratory. -Before any study-specific procedure is performed, the appropriate written informed consent must be obtained. |
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E.4 | Principal exclusion criteria |
-Diagnosis of breast or prostate cancer -Current or prior IV bisphosphonate administration -Current or prior oral bisphosphonate for the treatment of bone metastasis / osteolytic lesion -Planned radiation therapy or surgery to bone -Prior administration of denosumab -Known brain metastases -Life expectancy less than 6 months -Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw -Active dental or jaw condition which requires oral surgery -Non-healed dental/oral surgery -Planned invasive dental procedure over the course of the study -Evidence of any of the following conditions per subject self report or medical chart review: a) any other prior malignancy (other than basal cell carcinoma, or in situ cervical cancer) with active disease within 3 years before randomization b) known infection with human immunodeficiency virus c)active infection with Hepatitis B or Hepatitis C virus -Any organic or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results -Thirty days or less since receiving an investigational product or device (ie, does not have marketing authorization; thalidomide use is allowed) in another clinical trial -Pregnant or breast-feeding women -Subject with reproductive potential who will not agree to use effective contraception (as defined by the principal investigator or designee) -Known sensitivity to any of the products to be administered during the study (eg, zoledronic acid, mammalian derived products, calcium or vitamin D) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to the first on-study SRE (non-inferiority). SRE is an aggregate endpoint that includes pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. |
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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 | Information not present in EudraCT |
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) | 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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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End of study is defined as 4 weeks after the anticipated date that the 745th subject experiences their first on-study SRE.
After the end of study visit, follow-up survival information will be collected by clinic visit or telephone contact every 12 weeks (± 14 days) for 2 years after the end of study visit. Additionally, a serum sample to evaluate for the presence of anti-denosumab antibodies is to be obtained 24 weeks (approximately 6 months) after the end of study visit. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |