E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Giant cell tumor of bone (GCTB) |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10005968 |
E.1.2 | Term | Bone giant cell tumor |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety profile of denosumab in subjects with GCTB |
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E.2.2 | Secondary objectives of the trial |
- Evaluation of time to disease progression in subjects with unsalvageable GCTB treated with denosumab (cohort 1)
- Evaluation of the proportion of subjects who do not require surgery in denosumab treated subjects with salvageable GCTB (cohort 2)
- to evaluate denosumab pharmacokinetics (PK) in adolescent and adult subjects with GCTB (PK subset) |
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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 |
Pharmacokinetic substudy introduced as part of Protocol Amendment 7 dated 15 May 2013:
Serum samples (for serum denosumab concentration levels and sCTx) and urine samples (for urinary N-telopeptide [uNTx]; urine analytes will include creatinine and raw N-telopeptide [NTx]) will be obtained on a subset of approximately 20 subjects (approximately
10 adolescent and 10 adult subjects) at baseline (prior to administration of investigational product on study day 1) and on study as outlined in the schedule of assessments (Appendix A) of the protocol. Amgen Inc or its designee will be responsible for analyzing these samples and will measure urine creatinine.
The primary purpose of this substudy is to provide sufficient PK data to empirically compare trough exposures between 10 adolescent and 10 adult patients through steady-state (month 4). |
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E.3 | Principal inclusion criteria |
- Pathologically confirmed giant cell tumor of bone within 1 year before study enrollment
- Measurable evidence of active disease within 1 year before study enrollment
- Subjects with surgically unsalvageable disease (eg, sacral, spinal GCT, or multiple lesions including pulmonary metastases) OR subjects whose planned initial surgery includes joint resection, limb amputation, hemipelvectomy or surgical procedure resulting in severe morbidity, other than curettage with complete resection of tumor
- Karnofsky performance status ≥ 50% (ie, ECOG status 0, 1, or 2)
- Adults or skeletally mature adolescents (ie, radiographic evidence of at least 1 mature long bone [eg, humerous with closed growth epiphyseal plate]) ≥ 12 years of age
- Skeletally mature adolescents must weigh at least 45 kg
- Before any study-specific procedure is performed, the appropriate written informed consent must be obtained.
Inclusion Criteria for 20040215 subjects:
- Subjects currently enrolled in study 20040215
- Before any study-specific procedure is performed, the appropriate written informed consent must be obtained |
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E.4 | Principal exclusion criteria |
- Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, or embolization)
- Concurrent bisphosphonate treatment
- Known or suspected current diagnosis of underlying malignancy including high-grade sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma
- Known or suspected current diagnosis of non GCTB giant cell-rich tumors
- Known or suspected current diagnosis of brown cell tumor of bone or Paget’s disease
- Known diagnosis of second malignancy within the past 5 years (subjects with definitively treated basal cell carcinoma and cervical carcinoma in situ are permitted)
- Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
- Active dental or jaw condition which requires oral surgery, including tooth extraction
- Non-healed dental/oral surgery
- Planned invasive dental procedure for the course of the study
- Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(ies), or subject is receiving other investigational agent(s)
- Subject has known sensitivity to any of the products to be administered during dosing
- Unstable systemic disease including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before enrollment
- Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment
- Female subject of child bearing potential is not willing to use two methods of highly effective contraception during treatment and for 5 months after the end of treatment
- Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
Exclusion Criteria for 20040215 subjects:
- Developed sensitivity to mammalian cell derived drug products during the 20040215 study
- Currently receiving any unapproved investigational product other than denosumab
- Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment
- Female subject of child bearing potential is not willing to use two methods of highly effective contraception during treatment and for 5 months after the end of treatment
- Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety profile of denosumab characterized in terms of the type, frequency, and severity of adverse events and laboratory abnormalities for each cohort of the study. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analyses and final analysis |
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E.5.2 | Secondary end point(s) |
1- Time to disease progression for cohort 1
2- Proportion of subjects without any surgery at month 6 for cohort 2
3- Serum denosumab (trough) concentrations (PK subset) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- Interim analyses and final analysis
2- Month 6
3- Month 6 |
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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 | No |
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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
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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
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The end of the clinical trial for all subjects will occur when subjects enrolled through November 2012 (before Amendment 7) have completed at least 60 months on study, or until death or lost to follow-up, whichever comes first. Study enrollment (prior to Amendment 7) concluded in November 2012; therefore the final study visits will be conducted and the study is anticipated to end by approximately November 2017. |
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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 | 9 |
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 | 9 |
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 |