E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic castrate-resistant prostate cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062904 |
E.1.2 | Term | Hormone-refractory prostate cancer |
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 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 hormone-refractory prostate cancer and bone metastases. SRE is defined as pathological fracture (vertebral or nonvertebral), 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 first on-study SRE
-To determine if denosumab is superior to zoledronic acid with respect to 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 | No |
E.3 | Principal inclusion criteria |
-Men greater than or equal to 18 years of age with histologically-confirmed prostate cancer.
-Current or prior radiographic (ie, x-ray, computer tomography [CT], or magnetic resonance imaging [MRI]) evidence of at least 1 bone metastasis.
-Documented failure of at least one hormonal therapy as evidenced by a rising PSA (ie, 3 consecutive determinations, taken at least 2 weeks apart from one another. The third measurement must be greater than or equal to 0.4 ng/mL and taken within 8 weeks prior to randomization).
-Serum testosterone level of < 50 ng/dL due to either surgical or chemical castration
-Eastern Cooperative Oncology Group (ECOG) performance status of 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 institutional 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 (Cockcroft-Gault) 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)
-Before any study-specific procedure is performed, the appropriate written informed consent must be obtained.
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E.4 | Principal exclusion criteria |
-Current or prior IV bisphosphonate administration for any reason
-Current or prior oral bisphosphonate administration for the treatment of bone metastases
-Planned radiation therapy or surgery to bone
-Prior administration of denosumab
-Known brain metastasis
-Life expectancy less than 6 months
-Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
-Active dental or jaw condition that requires oral surgery
-Non-healed dental/oral surgery
-Planned invasive dental procedure(s) for the course of the study
-Evidence of any of the following conditions per subject self report or medical chart review:
1. Known history of second malignancy within the past 3 years, except for basal cell carcinoma
2. Known infection with human immunodeficiency virus
3. Active infection with hepatitis B or hepatitis C virus
-Any 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) in another clinical trial
-Subject with reproductive potential who will not agree to use effective contraception (as defined by the investigator or designee)
-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(s) (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.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis cut-off date is event-driven (i.e. when approximately
745 subjects have experienced an on-study SRE) |
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E.5.2 | Secondary end point(s) |
- Time to the first on-study SRE (superiority)
- Time to first-and-subsequent on-study SRE (superiority)
- Subject incidence of treatment-emergent adverse events
- Changes in laboratory values
- Incidence of anti-denosumab antibody (binding and neutralizing) formation |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Analysis cut-off date is event-driven (i.e. when approximately 745
subjects have experienced an on-study SRE) |
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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 | No |
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.8.2.4 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 148 |
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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
Costa Rica |
India |
Israel |
Mexico |
New Zealand |
Panama |
Peru |
Russian Federation |
South Africa |
Switzerland |
Turkey |
Ukraine |
United States |
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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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If the benefit: risk of denosumab is positive, the end of the study is defined as 4 weeks after the last dose of denosumab in the open-label treatment phase. If the benefit:risk is not positive, the end of study is defined as 4 weeks after the last dose of investigational product in 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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |