Study of Denosumab in Subjects With Giant Cell Tumor of Bone

Study Overview
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Brief Summary
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To determine how safe denosumab is in treating subjects with giant cell tumor of bone (GCTB)

Detailed Description
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To determine how safe denosumab is in treating subjects with GCTB

Official Title
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An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects With Giant Cell Tumor of Bone

Conditions
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Cancer, Giant Cell Tumors, Giant Cell Tumor of Bone, Benign Giant Cell Tumors

Intervention / Treatment
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* Drug: Denosumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologically confirmed GCTB 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 GCTB, or multiple lesions including pulmonary metastases) OR subjects whose planned surgery includes joint resection, limb amputation, hemipelvectomy or surgical procedure resulting in severe morbidity Karnofsky performance status equal or greater than 50% (ie, Eastern Cooperative Oncology Group status 0, 1, or 2) Adults or skeletally mature adolescents (ie, radiographic evidence of at least 1 mature long bone [eg, humerus with closed growth epiphyseal plate]) equal or greater than 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 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(s), 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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15. | Drug: Denosumab<br>* 120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.<br>* Other names: AMG 162, Immunoglobulin G2 human monoclonal antibody to RANK ligand;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | AE defined as any untoward medical occurrence in a clinical trial participant. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results are presented for treatment-emergent events (TEAEs) and included all AEs occurring from first dose in initial treatment phase to end of initial treatment phase (or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase). | From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months). | 
| Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively. | Baseline (day 1) up to last study visit for initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | Time to disease progression or recurrence during the on-study period was defined as the time interval (in days) from the date of first dose of study drug to the date of earliest Progressive Disease (PD) during the initial treatment phase. PD was defined as the response of progressive disease, locally recurrent disease or relapse as captured in the Disease Status page of the Case Report Form. If a participant had not had PD by the end of the initial treatment phase date, time to disease progression or recurrence were censored at her/his end of initial treatment phase date. Since median time to disease progression or recurrence for participants in cohort 1 was not reached, Kaplan-Meier estimates for the probability (expressed as a percentage) of participants in cohort 1 to have disease progression or recurrence at months 6, 12, 24, 36 and 60 are presented. | From first dose of study drug up to the end of the initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months). | 
| Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2 | The percentage of participants without any surgery at month 6 was equivalent to the number of participants without any surgery by month 6 divided by the number of cohort 2 participants who had an opportunity to complete 6 months of treatment, expressed as a percentage. | At month 6. | 
| Mean Serum Denosumab Trough Concentrations | Blood samples for determination of serum denosumab concentration levels were obtained from participants included in the pharmacokinetic (PK) substudy at baseline (prior to administration of study drug on day 1) and at scheduled time points during the study up to week 25. | Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Giant Cell Tumor of Bone