Bone Metastases
Conditions
Keywords
Fractures, Compressions, Bisphosphonates, Bone metastases, Breast cancer, Skeletal, Radiation, Surgery to Bone
Brief summary
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone metastases in subjects with advanced breast cancer.
Interventions
BIOLOGICALDenosumab
Q4W 120 mg denosumab SC injection and 4 mg zoledronic acid (Zometa) placebo IV over a minimum of 15 minutes
DRUGZoledronic Acid
Q4W 4 mg zoledronic acid IV over minimum 15 minutes and 120 mg denosumab placebo SC
Sponsors
Daiichi Sankyo
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults with histologically or cytologically confirmed breast adenocarcinoma * radiographic evidence of at least one bone mets * Easter Cooperative Oncology Group status of 0, 1 or 2; * adequate organ function
Exclusion criteria
* Current or prior IV bisphosphonate administration * current or prior oral bisphosphonates for bone mets * life expectancy of less than 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First On-Study Skeletal Related Event (SRE) (Non-inferiority) | Up to 34 months | Time to first on-study skeletal-related event (SRE) using a non-inferiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First On-Study Skeletal-Related Event (Superiority) | Up to 34 months | Time to first on-study skeletal-related event (SRE) using a superiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented. |
| Time to First and Subsequent On-Study Skeletal-Related Event | Up to 34 months | Time to first and subsequent on-study skeletal-related event (SRE) using a 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 number of events. |
Participant flow
Recruitment details
Participants were enrolled from 27 April 2006 through 31 December 2007
Pre-assignment details
2049 patients were enrolled in the study, but 3 patients were excluded from all analyses because properly documented informed consent was not obtained.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with subcutaneous denosumab placebo once every 4 weeks | 1,020 |
| Denosumab Denomsumab 120 mg subcutaneously with intravenous zoledronic acid placebo once every 4 weeks | 1,026 |
| Total | 2,046 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 43 | 28 |
| Overall Study | Death | 169 | 174 |
| Overall Study | Disease progression | 124 | 124 |
| Overall Study | Ineligibility determined | 2 | 1 |
| Overall Study | Lost to Follow-up | 7 | 8 |
| Overall Study | Noncompliance | 4 | 10 |
| Overall Study | Other | 21 | 18 |
| Overall Study | Participant request | 57 | 61 |
| Overall Study | Physician Decision | 15 | 14 |
| Overall Study | Protocol deviation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 117 | 118 |
Baseline characteristics
| Characteristic | Denosumab | Zoledronic Acid | Total |
|---|---|---|---|
| Age, Continuous | 56.8 Years STANDARD_DEVIATION 11.5 | 56.6 Years STANDARD_DEVIATION 11.6 | 56.7 Years STANDARD_DEVIATION 11.5 |
| Current Chemotherapy Stratification Factor No | 616 Participants | 612 Participants | 1228 Participants |
| Current Chemotherapy Stratification Factor Yes | 410 Participants | 408 Participants | 818 Participants |
| Japan Stratification Factor No | 957 Participants | 953 Participants | 1910 Participants |
| Japan Stratification Factor Yes | 69 Participants | 67 Participants | 136 Participants |
| Previous Skeletal-Related Event Stratification Factor No | 648 Participants | 647 Participants | 1295 Participants |
| Previous Skeletal-Related Event Stratification Factor Yes | 378 Participants | 373 Participants | 751 Participants |
| Prior Oral Bisphosphonate Use Stratification Factor No | 984 Participants | 982 Participants | 1966 Participants |
| Prior Oral Bisphosphonate Use Stratification Factor Yes | 42 Participants | 38 Participants | 80 Participants |
| Race/Ethnicity, Customized Asian | 32 Participants | 37 Participants | 69 Participants |
| Race/Ethnicity, Customized Black or African American | 26 Participants | 25 Participants | 51 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 59 Participants | 59 Participants | 118 Participants |
| Race/Ethnicity, Customized Japanese | 70 Participants | 69 Participants | 139 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 16 Participants | 16 Participants | 32 Participants |
| Race/Ethnicity, Customized White or Caucasian | 822 Participants | 813 Participants | 1635 Participants |
| Sex: Female, Male Female | 1018 Participants | 1011 Participants | 2029 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 941 / 1,013 | 924 / 1,020 |
| serious Total, serious adverse events | 471 / 1,013 | 453 / 1,020 |
Outcome results
Primary
Time to First On-Study Skeletal Related Event (SRE) (Non-inferiority)
Time to first on-study skeletal-related event (SRE) using a non-inferiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.
Time frame: Up to 34 months
Population: Full Analysis Set, composed of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to First On-Study Skeletal Related Event (SRE) (Non-inferiority) | 372 Participants |
| Denosumab | Time to First On-Study Skeletal Related Event (SRE) (Non-inferiority) | 315 Participants |
p-value: <0.000195% CI: [0.71, 0.95]Regression, Cox
Secondary
Time to First and Subsequent On-Study Skeletal-Related Event
Time to first and subsequent on-study skeletal-related event (SRE) using a 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 number of events.
Time frame: Up to 34 months
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to First and Subsequent On-Study Skeletal-Related Event | 608 Events |
| Denosumab | Time to First and Subsequent On-Study Skeletal-Related Event | 474 Events |
p-value: 0.00195% CI: [0.66, 0.89]Anderson-Gill model
Secondary
Time to First On-Study Skeletal-Related Event (Superiority)
Time to first on-study skeletal-related event (SRE) using a superiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.
Time frame: Up to 34 months
Population: Full Analysis Set, composed of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to First On-Study Skeletal-Related Event (Superiority) | 372 Participants |
| Denosumab | Time to First On-Study Skeletal-Related Event (Superiority) | 315 Participants |
p-value: 0.0195% CI: [0.71, 0.95]Regression, Cox