E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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 | 14.1 |
E.1.2 | Level | PT |
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 compare the treatment effect of denosumab with placebo on prolonging bone metastasis-free survival in men with hormone refractory (androgen independent) prostate cancer who have no bone metastasis at baseline. |
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E.2.2 | Secondary objectives of the trial |
To compare the treatment effect of denosumab with placebo on:
• time to first bone metastasis excluding deaths
• overall survival
To assess the safety and tolerability of denosumab compared with placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Men with histologically confirmed prostate cancer
-Age ≥ 18 years
-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-Chemical or surgical castration defined as:
• bilateral orchiectomy (also referred to as orchidectomy) at least 6 months before randomization, OR
• continuous androgen deprivation therapy (ADT) with a gonadotropin releasing hormone (GnRH) agonist or antagonist for at least 6 months before randomisation
-Total serum testosterone level of < 50 ng/dL (1.72 nmol/L)
-Hormone refractory (androgen independent) prostate cancer demonstrated during continuous ADT/post-orchiectomy defined as:
• 3 consecutive PSA values with PSA1 < PSA2 < PSA3
• each PSA value must be separated by at least 2 weeks
• PSA2 and PSA3 ≥ 1.0 ng/mL
-High risk for development of bone metastasis defined as:
• PSA value ≥ 8.0 ng/mL, obtained no more than 3 months before randomisation
OR
• PSA doubling time ≤ 10.0 months
-Adequate organ function as defined by the following criteria:
• Serum aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
• Serum alanine aminotransferase (ALT) ≤ 2.5 x ULN
• Serum total bilirubin ≤ 1.5 x ULN
• Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL)
-Before any study-specific procedure, the appropriate written informed consent must be obtained |
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E.4 | Principal exclusion criteria |
-Prior or current evidence of radiographically detectable bone metastasis
-Known prior or current evidence of any metastatic involvement of distant organs (lymph node metastases in any region is acceptable)
-Prior or current IV bisphosphonate administration
-Prior or current use of oral bisphosphonates as follows:
• Greater than or equal to 3 years continuously
• Greater than 3 months but less than 3 years (eligible if subject has a 1 year washout before randomisation)
-Prior administration of AMG 162
-Prior history or current evidence of osteomyelitis or osteonecrosis of the jaw
-Evidence of any of the following conditions per subject self report or medical chart review:
• Any prior malignancy (other than treated basal cell skin cancer), within 5 years before randomization
• Major surgery or significant traumatic injury occurring within 4 weeks before randomisation
• Active infection with Hepatitis B virus or Hepatitis C virus
• Known infection with human immunodeficiency virus (HIV)
-Any major medical 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 in another clinical trial.
-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) |
Bone metastasis-free survival determined by the time to first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause |
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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 660 subjects have developped bone metastasis or died) |
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E.5.2 | Secondary end point(s) |
• Time to first bone metastasis (either symptomatic or asymptomatic) excluding death
• Overall survival time
• Subject incidence of treatment-emergent adverse events
• Changes in laboratory values
• Subject incidence of anti-denosumab neutralizing antibody 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 660 subjects have developped bone metastasis or died) |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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) | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 106 |
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 |
Argentina |
Australia |
Brazil |
Canada |
European Union |
India |
Mexico |
New Zealand |
Russian Federation |
Ukraine |
Serbia |
South Africa |
Switzerland |
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
|
If the benefit:risk is positive, the end of 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 | 7 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |