Benign Giant Cell Tumors, Cancer, Giant Cell Tumor of Bone, Giant Cell Tumors
Conditions
Keywords
Giant Cell Tumor of Bone
Brief summary
To determine how safe denosumab is in treating subjects with giant cell tumor of bone (GCTB)
Detailed description
To determine how safe denosumab is in treating subjects with GCTB
Interventions
DRUGDenosumab
120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months). | 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). |
| Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | 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). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | 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). | 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. |
| Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2 | At month 6. | 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. |
| Mean Serum Denosumab Trough Concentrations | Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25. | 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. |
Countries
Australia, Austria, Canada, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Adults and skeletally mature adolescents (≥12 years of age) were enrolled in this open-label single-arm study. The study was conducted at 30 centers in North America, Europe, and Australia from 09 Sep 2008 to study completion on 17 May 2018. The planned study duration for each participant was at least 60 months (following protocol amendment 7).
Pre-assignment details
3 participants from study 20040215 (NCT00396279) were enrolled directly into safety follow-up phase without retreatment. They were excluded from all defined analysis sets and results are reported for the 532 participants enrolled into the treatment phase. Non-completion reasons are summarized for the on-study period (ie, initial treatment phase).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Denosumab 120 mg Q4W) Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment. | 268 |
| Cohort 2 (Denosumab 120 mg Q4W) Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment. | 252 |
| Cohort 3 (Denosumab 120 mg Q4W) Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment. | 12 |
| Total | 532 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative Decision | 83 | 42 | 5 |
| Overall Study | Adverse Event | 21 | 19 | 1 |
| Overall Study | Complete Resection (as per protocol) | 25 | 121 | 0 |
| Overall Study | Death | 5 | 1 | 0 |
| Overall Study | Disease Progression | 21 | 9 | 0 |
| Overall Study | End of Trial | 32 | 12 | 3 |
| Overall Study | Ineligibility Determined | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 12 | 14 | 0 |
| Overall Study | Noncompliance | 4 | 6 | 0 |
| Overall Study | Other | 19 | 14 | 1 |
| Overall Study | Pregnancy | 5 | 0 | 1 |
| Overall Study | Requirement for Alternative Therapy | 8 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 33 | 11 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 (Denosumab 120 mg Q4W) | Cohort 2 (Denosumab 120 mg Q4W) | Cohort 3 (Denosumab 120 mg Q4W) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 14 Participants | 14 Participants | 0 Participants | 28 Participants |
| Age, Categorical >=65 years | 16 Participants | 7 Participants | 0 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 238 Participants | 231 Participants | 12 Participants | 481 Participants |
| Age, Continuous | 36.4 Years STANDARD_DEVIATION 14.6 | 35.1 Years STANDARD_DEVIATION 13.5 | 36.1 Years STANDARD_DEVIATION 14.9 | 35.8 Years STANDARD_DEVIATION 14.1 |
| GCTB Disease Type Primary resectable | 0 Participants | 167 Participants | 0 Participants | 167 Participants |
| GCTB Disease Type Primary unresectable | 93 Participants | 0 Participants | 2 Participants | 95 Participants |
| GCTB Disease Type Recurrent resectable | 0 Participants | 85 Participants | 0 Participants | 85 Participants |
| GCTB Disease Type Recurrent unresectable | 175 Participants | 0 Participants | 10 Participants | 185 Participants |
| Race/Ethnicity, Customized Asian | 11 Participants | 14 Participants | 0 Participants | 25 Participants |
| Race/Ethnicity, Customized Black or African American | 18 Participants | 12 Participants | 0 Participants | 30 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 Participants | 13 Participants | 1 Participants | 27 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 4 Participants | 0 Participants | 9 Participants |
| Race/Ethnicity, Customized White or Caucasian | 221 Participants | 208 Participants | 11 Participants | 440 Participants |
| Sex: Female, Male Female | 154 Participants | 142 Participants | 5 Participants | 301 Participants |
| Sex: Female, Male Male | 114 Participants | 110 Participants | 7 Participants | 231 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 26 / 526 |
| other Total, other adverse events | 480 / 526 |
| serious Total, serious adverse events | 176 / 526 |
Outcome results
Primary
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.
Time frame: 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).
Population: The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 4 (Below) | 2 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Albumin Grade 3 (Below) | 1 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Magnesium Grade 3 (Above) | 4 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Phosphate Grade 3 (Below) | 60 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 3 (Above) | 0 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Creatinine Grade 3 (Above) | 0 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 3 (Below) | 1 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 4 (Above) | 1 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Magnesium Grade 3 (Below) | 1 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Phosphate Grade 3 (Below) | 41 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 3 (Above) | 1 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 4 (Above) | 1 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 3 (Below) | 0 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 4 (Below) | 0 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Magnesium Grade 3 (Above) | 5 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Magnesium Grade 3 (Below) | 0 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Creatinine Grade 3 (Above) | 1 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Albumin Grade 3 (Below) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 3 (Below) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 3 (Above) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Magnesium Grade 3 (Below) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 4 (Above) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Albumin Grade 3 (Below) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Phosphate Grade 3 (Below) | 4 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Calcium corrected Grade 4 (Below) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Creatinine Grade 3 (Above) | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters | Magnesium Grade 3 (Above) | 2 Participants |
Primary
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).
Time frame: From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months).
Population: The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 98 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to study drug discontinuation | 27 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to treatment phase discontinuation | 27 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 260 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE related to study drug | 184 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | CTCAE Grade 3, 4, or 5 | 121 Participants |
| Cohort 1 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fatal TEAE | 8 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to treatment phase discontinuation | 24 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 231 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 39 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fatal TEAE | 3 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to study drug discontinuation | 23 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | CTCAE Grade 3, 4, or 5 | 59 Participants |
| Cohort 2 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE related to study drug | 136 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to study drug discontinuation | 1 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 5 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE related to study drug | 9 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | CTCAE Grade 3, 4, or 5 | 6 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to treatment phase discontinuation | 1 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| Cohort 3 (Denosumab 120 mg Q4W) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 12 Participants |
Secondary
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.
Time frame: Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25.
Population: The PK analysis set included all participants who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement. Only participants with available data at each time point were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 17 | 23600 nanograms / milliliter | Standard Deviation 4370 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Day 8 | 11800 nanograms / milliliter | Standard Deviation 4130 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Day 15 | 21800 nanograms / milliliter | Standard Deviation 5620 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 5 | 30400 nanograms / milliliter | Standard Deviation 6150 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 9 | 25100 nanograms / milliliter | Standard Deviation 6450 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 13 | 22300 nanograms / milliliter | Standard Deviation 6840 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 25 | 22400 nanograms / milliliter | Standard Deviation 6690 |
| Cohort 1 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Day 1 | 0.0 nanograms / milliliter | Standard Deviation 0 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 13 | 29100 nanograms / milliliter | Standard Deviation 10000 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Day 1 | 0.0 nanograms / milliliter | Standard Deviation 0 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 9 | 30000 nanograms / milliliter | Standard Deviation 10300 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Day 8 | 12000 nanograms / milliliter | Standard Deviation 4300 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 25 | 25400 nanograms / milliliter | Standard Deviation 10800 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Day 15 | 24200 nanograms / milliliter | Standard Deviation 9050 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 17 | 28300 nanograms / milliliter | Standard Deviation 11600 |
| Cohort 2 (Denosumab 120 mg Q4W) | Mean Serum Denosumab Trough Concentrations | Week 5 | 33500 nanograms / milliliter | Standard Deviation 8970 |
Secondary
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.
Time frame: At month 6.
Population: The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 2 only for those who had the opportunity to be on-study for at least 6 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Denosumab 120 mg Q4W) | Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2 | 92.0 Percentage of participants |
Secondary
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.
Time frame: 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).
Population: The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 1 only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Denosumab 120 mg Q4W) | Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | Month 6 | 1.9 Percent probability |
| Cohort 1 (Denosumab 120 mg Q4W) | Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | Month 12 | 4.3 Percent probability |
| Cohort 1 (Denosumab 120 mg Q4W) | Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | Month 24 | 6.1 Percent probability |
| Cohort 1 (Denosumab 120 mg Q4W) | Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | Month 36 | 8.2 Percent probability |
| Cohort 1 (Denosumab 120 mg Q4W) | Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability | Month 60 | 11.7 Percent probability |