Bone Metastases
Conditions
Keywords
Bone metastases, lytic bone lesions, advanced cancer, multiple myeloma, lymphoma, solid tumors, skeletal related events, skeletal fractures, spinal cord compressions, radiation to bone, surgery to bone, bisphosphonates, denosumab
Brief summary
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid (Zometa®) in the treatment of bone metastases (lytic bone lesions from multiple myeloma) in subjects with advanced cancer and multiple myeloma (excluding breast and prostate cancer)
Interventions
BIOLOGICALDenosumab
120 milligrams by subcutaneous injection every 4 weeks
DRUGZoledronic Acid
4 milligrams intravenous Zoledronic Acid over minimum 15 minutes every 4 weeks
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults with histologically/cystologically confirmed advanced cancers including solid tumors, multiple myeloma, and lymphoma * Radiographic evidence of at least one bone metastasis (or lytic bone lesion from multiple myeloma); ECOG performance status 0, 1, or 2 * Adequate organ function
Exclusion criteria
* Diagnosis of breast or prostate cancer * Current or prior intravenous bisphosphonate administration * Current or prior oral bisphosphonates for bone metastases, life expectancy of less than 6 months * Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First On-Study Skeletal-Related Event (Non-Inferiority) | up to 33 months | Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First On-Study Skeletal-Related Event (Superiority) | up to 33 months | Time to first on-study skeletal-related event (SRE) using a test for superiority. Median was estimated using the Kaplan-Meier method. |
| Time to the First-and-Subsequent On-Study Skeletal-Related Event | up to 33 months | Time to the first-and-subsequent on-study skeletal-related event (SRE) using multiple event analysis. To be considered a subsequent SRE, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative mean number of events. |
Participant flow
Recruitment details
Participants were enrolled from 21 June 2006 through 16 May 2008
Pre-assignment details
A total of 1779 participants were enrolled in the study. Three participants from one site were excluded from all analyses because Institutional Review Board (IRB) review activities and oversight were not ensured.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks | 890 |
| Denosumab Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks | 886 |
| Total | 1,776 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 48 | 36 |
| Overall Study | Death | 316 | 310 |
| Overall Study | Disease progression | 104 | 126 |
| Overall Study | Ineligibility determined | 2 | 1 |
| Overall Study | Lost to Follow-up | 16 | 22 |
| Overall Study | Noncompliance | 15 | 17 |
| Overall Study | Other | 36 | 44 |
| Overall Study | Participant request | 31 | 22 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol deviation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 143 | 124 |
Baseline characteristics
| Characteristic | Total | Zoledronic Acid | Denosumab |
|---|---|---|---|
| Age, Continuous | 59.9 Years STANDARD_DEVIATION 11.1 | 60.6 Years STANDARD_DEVIATION 10.7 | 59.3 Years STANDARD_DEVIATION 11.4 |
| Previous Skeletal-Related Event Stratification Factor No | 890 Participants | 444 Participants | 446 Participants |
| Previous Skeletal-Related Event Stratification Factor Yes | 886 Participants | 446 Participants | 440 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 80 Participants | 44 Participants | 36 Participants |
| Race/Ethnicity, Customized Black or African American | 49 Participants | 29 Participants | 20 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 85 Participants | 36 Participants | 49 Participants |
| Race/Ethnicity, Customized Japanese | 4 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 16 Participants | 8 Participants | 8 Participants |
| Race/Ethnicity, Customized White or Caucasian | 1540 Participants | 770 Participants | 770 Participants |
| Sex: Female, Male Female | 636 Participants | 338 Participants | 298 Participants |
| Sex: Female, Male Male | 1140 Participants | 552 Participants | 588 Participants |
| Systematic Anti-Cancer Therapy Stratification Factor No | 283 Participants | 143 Participants | 140 Participants |
| Systematic Anti-Cancer Therapy Stratification Factor Yes | 1493 Participants | 747 Participants | 746 Participants |
| Tumor Type Stratification Factor Multiple myeloma | 179 Participants | 93 Participants | 86 Participants |
| Tumor Type Stratification Factor Non-small cell lung cancer | 688 Participants | 345 Participants | 343 Participants |
| Tumor Type Stratification Factor Other | 909 Participants | 452 Participants | 457 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 767 / 878 | 751 / 878 |
| serious Total, serious adverse events | 581 / 878 | 552 / 878 |
Outcome results
Primary
Time to the First On-Study Skeletal-Related Event (Non-Inferiority)
Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method.
Time frame: up to 33 months
Population: Full Analysis Set, composed of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Time to the First On-Study Skeletal-Related Event (Non-Inferiority) | 496.0 Days |
| Denosumab | Time to the First On-Study Skeletal-Related Event (Non-Inferiority) | 625.0 Days |
p-value: 0.000795% CI: [0.71, 0.98]Regression, Cox
Secondary
Time to First On-Study Skeletal-Related Event (Superiority)
Time to first on-study skeletal-related event (SRE) using a test for superiority. Median was estimated using the Kaplan-Meier method.
Time frame: up to 33 months
Population: Full Analysis Set, composed of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Time to First On-Study Skeletal-Related Event (Superiority) | 496.0 Days |
| Denosumab | Time to First On-Study Skeletal-Related Event (Superiority) | 625.0 Days |
p-value: 0.0695% CI: [0.71, 0.98]Regression, Cox
Secondary
Time to the First-and-Subsequent On-Study Skeletal-Related Event
Time to the first-and-subsequent on-study skeletal-related event (SRE) using multiple event analysis. To be considered a subsequent SRE, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative mean number of events.
Time frame: up to 33 months
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to the First-and-Subsequent On-Study Skeletal-Related Event | 436 Events |
| Denosumab | Time to the First-and-Subsequent On-Study Skeletal-Related Event | 392 Events |
p-value: 0.14595% CI: [0.77, 1.04]Anderson-Gill model