E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of bone metastases in subjects with advanced breast cancer. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027452 |
E.1.2 | Term | Metastases to bone |
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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 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 breast cancer and bone metastases. 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 in subjects with advanced breast cancer and bone metastases. |
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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 | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: 20050136 - denosumab PK substudy Protocol date: 10 January 06 Serum denosumab concentration levels will be obtained from a subset of approximately 150 subjects prior to administration of the investigational products on study day 1, then on weeks 5, 9, 13, 25, 49, 73, 97, and at the end of study visit. The centers that will participate in this part of the study will be determined at the time of site selection on the basis of site interest, site ability to obtain and process serum denosumab concentration samples, and recruitment capacity. Objective: To measure serum concentration (trough) levels of denosumab |
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E.3 | Principal inclusion criteria |
- Adult (men included) with histologically or cytologically confirmed breast adenocarcinoma. - Current or prior radiographic (ie, x-ray, computer tomography [CT], or magnetic resonance imaging [MRI]) evidence of at least 1 bone metastasis. - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. - Adequate organ function as defined by the following criteria: 1. Serum aspartate aminotransferase (AST) less than or equal to 5 x upper limit of normal (ULN). 2. Serum alanine aminotransferase (ALT) less than or equal to 5 x ULN. 3. Serum total bilirubin less than or equal to 2 x ULN. 4. Creatinine clearance greater than or equal to 30 mL/min. 5. Albumin-adjusted serum calcium greater than or equal to 2.0 mmol/L (8.0 mg/dL) and less than or equal to 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, the appropriate written informed consent must be obtained. |
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E.4 | Principal exclusion criteria |
- Current or prior IV bisphosphonate administration. - Current or prior oral bisphosphonate treatment for bone metastasis. - 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 for the course of the study. - Evidence of any of the following conditions per subject self report or medical chart review: 1. Any prior malignancy (other than breast cancer, basal cell carcinoma, or in situ cervical cancer) with active disease within 3 years before randomization. 2. Known infection with human immunodeficiency virus. 3. Active infection with Hepatitis B or Hepatitis C virus. 4. 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. 5. Thirty days or less since receiving an investigational product or device (ie, does not have marketing authorization) in another clinical trial. 6. Subject with reproductive potential who will not agree to use effective contraception (as defined by the principal investigator or designee). 7. Known sensitivity to any of the products to be administered during dosing (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.8.5.1 | Number of sites anticipated in the EEA | 89 |
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 | 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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4 weeks after the last dose of investigational product at the end of the blinded treatment phase. |
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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 | 1 |
E.8.9.1 | In the Member State concerned days | |
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 | 1 |