Bone Metastases in Men With Hormone-Refractory Prostate Cancer, Bone Metastases in Subjects With Advanced Breast Cancer, Bone Metastases in Subjects With Advanced Cancer or Multiple Myeloma
Conditions
Keywords
Bone Metastases, AMG 162, Bisphosphonates, Solid Tumor Carcinomas, Advanced
Brief summary
The purpose of this trial is to determine the effectiveness of AMG 162 in reducing urinary N-telopeptide in advanced cancer subjects with bone metastases.
Interventions
GENETICAMG 162 180 mg (SC) q 12 weeks
A 180 mg AMG 162 (SC) administered every 12 weeks for 2 doses (Day 1 and wk 13) in the treatment phase. If subjected are enrolled in the extension phase, they will continue to receive a 180 mg AMG 162 (SC) administered every 12 weeks for 9 doses.
DRUGIV Bisphosphonate q 4 weeks
IV Bisphosphonate (eg pamidronate or zoledronic acid) every 4 weeks for 6 doses as described by package insert during the treatment phase. If enrolled to the extension phase, subject will be assigned to the AMG 162 180mg (SC) every 4 weeks for 26 doses.
GENETICAMG 162- 180 mg q 4 weeks
A 180 mg AMG 162 (SC) administered every 4 weeks for 6 doses in the treatment phase. If subjected are enrolled in the extension phase, they will continue to receive a 180 mg AMG 162 (SC) administered every 4 weeks for 26 doses.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients at least 18 years of age with histologically confirmed solid tumor carcinomas (except lung) or multiple myeloma * Radiographic evidence of 1 or more bone lesions or lytic lesion in myeloma * Currently receiving IV bisphosphonates * Urinary N-Telopeptide (uNTx) greater than 50 nM BCE/mM creatinine * Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2
Exclusion criteria
* More than 2 prior skeletal related events (SRE) * Known brain metastases * Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw * Active dental or jaw conditions which requires oral surgery * Non-healed dental/oral surgery * Prior administration of AMG 162 * Evidence of impending fracture in weight bearing bones * Pregnancy or breastfeeding. Subjects must be surgically sterile, postmenopausal, or must agree to use effective contraception during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13 | 13 weeks | Urinary N-telopeptide (uNTx) corrected by creatinine (uNTx/Cr) \< 50 nmol/mmol at week 13. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25 | Baseline, week 25 | Percent change from baseline to week 25 urinary N-telopeptide (uNTX) calculated using ((week 25 value - baseline value) / baseline value ) x 100. |
| Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol | Day 1, week 25 | Kaplan-Meier estimate of the median time from enrollment to the 1st occurrence of uNTx below 50 nmol BCE/mmol (corrected by creatinine) up to week 25. For participants whose uNTx does not go below 50 nM BCE/mM creatinine, the time is censored at time of last evaluation of uNTx by week 25. |
| Duration of Maintaining uNTX (Corrected by Creatinine) < 50nmol/mmol | Day 1, week 25 | Time from the 1st occurrence of uNTx below 50 nmol BCE/mmol (corrected by creatinine) to the 1st occurrence of uNTx above 50 nmol BCE/mmol up to week 25. For participants who remained below 50 nmol BCE/mmol, the time is censored at the time of last evaluation of uNTx up to week 25. |
| uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25 | 25 weeks | Urinary N-telopeptide (uNTX) corrected by creatinine \< 50 nmol/mmol at week 25. |
| Time to First Skeletal Related Event | Day 1, week 25 | Time from study day 1 to first Skeletal Related Event (SRE), defined as \>1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes). |
| Skeletal Related Events | Day 1, week 25 | Skeletal Related Event (SRE), defined as \>1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes). |
| Hypercalcemia | Day 1, week 25 | Occurrence of hypercalcemia at grade 3 or 4 according to CTCAE v3 criteria |
| Percent Change of Serum CTX From Baseline to Week 25 | Baseline, week 25 | Percent change from baseline to week 25 in Type I serum C-Telopeptide (CTX), calculated using ((week 25 value - baseline value) / baseline value ) x 100. |
Participant flow
Recruitment details
Participants were enrolled from 2 December 2004 through 30 March 2007
Participants by arm
| Arm | Count |
|---|---|
| Denosumab 180 mg Q4W Open-label denosumab 180 mg by subcutaneous injection once every 4 weeks (Q4W) | 38 |
| Bisphosphonate IV Q4W Open-label intravenous (IV) bisphosphonate once every 4 weeks (Q4W) | 37 |
| Denosumab 180 mg Q12W Open-label denosumab 180 mg by subcutaneous injection once every 12 weeks (Q12W) | 36 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Period | Adverse Event | 1 | 0 | 1 |
| Follow-up Period | Death | 6 | 6 | 4 |
| Follow-up Period | Disease progression | 3 | 1 | 0 |
| Follow-up Period | Lost to Follow-up | 0 | 1 | 2 |
| Follow-up Period | Other | 0 | 1 | 0 |
| Follow-up Period | Physician Decision | 1 | 1 | 0 |
| Follow-up Period | Withdrawal by Subject | 0 | 3 | 3 |
| Treatment Period (25 Weeks) | Death | 7 | 5 | 6 |
| Treatment Period (25 Weeks) | Disease progression | 2 | 3 | 2 |
| Treatment Period (25 Weeks) | Ineligibility determined | 0 | 1 | 0 |
| Treatment Period (25 Weeks) | Other | 1 | 0 | 0 |
| Treatment Period (25 Weeks) | Physician Decision | 0 | 0 | 1 |
| Treatment Period (25 Weeks) | Protocol deviation | 0 | 1 | 0 |
| Treatment Period (25 Weeks) | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Denosumab 180 mg Q4W | Denosumab 180 mg Q12W | Bisphosphonate IV Q4W |
|---|---|---|---|---|
| Age Continuous | 62.5 Years STANDARD_DEVIATION 11.8 | 60.6 Years STANDARD_DEVIATION 10.7 | 65.3 Years STANDARD_DEVIATION 12.7 | 61.6 Years STANDARD_DEVIATION 11.7 |
| Cancer Type Stratification Factor Breast cancer | 46 Participants | 16 Participants | 14 Participants | 16 Participants |
| Cancer Type Stratification Factor Mutiple myeloma | 9 Participants | 2 Participants | 4 Participants | 3 Participants |
| Cancer Type Stratification Factor Other solid tumor | 6 Participants | 3 Participants | 2 Participants | 1 Participants |
| Cancer Type Stratification Factor Prostate cancer | 50 Participants | 17 Participants | 16 Participants | 17 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 44 Participants | 16 Participants | 15 Participants | 13 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 63 Participants | 22 Participants | 19 Participants | 22 Participants |
| Serum C-Telopeptide (CTx) | 1.28 ng/mL STANDARD_DEVIATION 1.48 | 1.12 ng/mL STANDARD_DEVIATION 1.18 | 1.34 ng/mL STANDARD_DEVIATION 1.27 | 1.40 ng/mL STANDARD_DEVIATION 1.93 |
| Sex: Female, Male Female | 56 Participants | 19 Participants | 19 Participants | 18 Participants |
| Sex: Female, Male Male | 55 Participants | 19 Participants | 17 Participants | 19 Participants |
| Urinary N-telopeptide (uNTx) Level | 158.01 nmol/mmol STANDARD_DEVIATION 177.11 | 149.94 nmol/mmol STANDARD_DEVIATION 147.2 | 175.15 nmol/mmol STANDARD_DEVIATION 208.87 | 149.88 nmol/mmol STANDARD_DEVIATION 176.28 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 33 / 35 | 29 / 35 | 29 / 38 |
| serious Total, serious adverse events | 19 / 35 | 16 / 35 | 21 / 38 |
Outcome results
Primary
uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13
Urinary N-telopeptide (uNTx) corrected by creatinine (uNTx/Cr) \< 50 nmol/mmol at week 13.
Time frame: 13 weeks
Population: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13 | 10 Participants |
| Denosumab 180 mg Q12W | uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13 | 21 Participants |
| Denosumab 180 mg Q4W | uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 13 | 28 Participants |
p-value: <0.00195% CI: [3.35, 45.03]Cochran-Mantel-Haenszel
p-value: 0.00295% CI: [1.74, 16.36]Cochran-Mantel-Haenszel
95% CI: [60.8, 89.9]
95% CI: [45.1, 79.6]
95% CI: [14.6, 46.3]
Secondary
Duration of Maintaining uNTX (Corrected by Creatinine) < 50nmol/mmol
Time from the 1st occurrence of uNTx below 50 nmol BCE/mmol (corrected by creatinine) to the 1st occurrence of uNTx above 50 nmol BCE/mmol up to week 25. For participants who remained below 50 nmol BCE/mmol, the time is censored at the time of last evaluation of uNTx up to week 25.
Time frame: Day 1, week 25
Population: Treatment Phase Primary Analysis Subset. Median was not reached in at least 1 treatment arm. In lieu of the median, the number of subject whose uNTX (corrected by creatinine) less than 50nmol/mmol is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Duration of Maintaining uNTX (Corrected by Creatinine) < 50nmol/mmol | 25 Participants |
| Denosumab 180 mg Q12W | Duration of Maintaining uNTX (Corrected by Creatinine) < 50nmol/mmol | 32 Participants |
| Denosumab 180 mg Q4W | Duration of Maintaining uNTX (Corrected by Creatinine) < 50nmol/mmol | 35 Participants |
p-value: 0.00695% CI: [0.11, 0.687]Regression, Cox
p-value: 0.00195% CI: [0.076, 0.523]Regression, Cox
Secondary
Hypercalcemia
Occurrence of hypercalcemia at grade 3 or 4 according to CTCAE v3 criteria
Time frame: Day 1, week 25
Population: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Hypercalcemia | 0 Participants |
| Denosumab 180 mg Q12W | Hypercalcemia | 0 Participants |
| Denosumab 180 mg Q4W | Hypercalcemia | 0 Participants |
Secondary
Percent Change of Serum CTX From Baseline to Week 25
Percent change from baseline to week 25 in Type I serum C-Telopeptide (CTX), calculated using ((week 25 value - baseline value) / baseline value ) x 100.
Time frame: Baseline, week 25
Population: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx and had available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change of Serum CTX From Baseline to Week 25 | -40.68 Percent change | Standard Deviation 38.93 |
| Denosumab 180 mg Q12W | Percent Change of Serum CTX From Baseline to Week 25 | -76.74 Percent change | Standard Deviation 19.74 |
| Denosumab 180 mg Q4W | Percent Change of Serum CTX From Baseline to Week 25 | -68.39 Percent change | Standard Deviation 36.15 |
p-value: 0.056ANCOVA
Secondary
Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25
Percent change from baseline to week 25 urinary N-telopeptide (uNTX) calculated using ((week 25 value - baseline value) / baseline value ) x 100.
Time frame: Baseline, week 25
Population: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisphosphonate IV Q4W | Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25 | -32.91 Percent change | Standard Deviation 65.91 |
| Denosumab 180 mg Q12W | Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25 | -69.09 Percent change | Standard Deviation 29.97 |
| Denosumab 180 mg Q4W | Percent Change of uNTx (Corrected by Creatinne) From Baseline to Week 25 | -41.68 Percent change | Standard Deviation 118.32 |
p-value: 0.388ANCOVA
Secondary
Skeletal Related Events
Skeletal Related Event (SRE), defined as \>1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes).
Time frame: Day 1, week 25
Population: All participants exposed to investigational product during the treatment phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Skeletal Related Events | 6 Participants |
| Denosumab 180 mg Q12W | Skeletal Related Events | 4 Participants |
| Denosumab 180 mg Q4W | Skeletal Related Events | 2 Participants |
95% CI: [0.05, 1.44]
95% CI: [0.08, 1.76]
Secondary
Time to First Skeletal Related Event
Time from study day 1 to first Skeletal Related Event (SRE), defined as \>1 of the following: pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone (including the use of radioisotopes).
Time frame: Day 1, week 25
Population: All participants exposed to investigational product during the treatment phase. Median was not reached in at least 1 treatment arm. In lieu of the median, the number of subject who experienced a skeletal related event is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | Time to First Skeletal Related Event | 6 Participants |
| Denosumab 180 mg Q12W | Time to First Skeletal Related Event | 4 Participants |
| Denosumab 180 mg Q4W | Time to First Skeletal Related Event | 2 Participants |
p-value: 0.10595% CI: [0.018, 1.465]Regression, Cox
p-value: 0.4395% CI: [0.143, 2.289]Regression, Cox
Secondary
Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol
Kaplan-Meier estimate of the median time from enrollment to the 1st occurrence of uNTx below 50 nmol BCE/mmol (corrected by creatinine) up to week 25. For participants whose uNTx does not go below 50 nM BCE/mM creatinine, the time is censored at time of last evaluation of uNTx by week 25.
Time frame: Day 1, week 25
Population: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bisphosphonate IV Q4W | Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol | 65 Days |
| Denosumab 180 mg Q12W | Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol | 9 Days |
| Denosumab 180 mg Q4W | Time to Reduction of uNTX (Corrected by Creatinine) to <50nmol/mmol | 10 Days |
p-value: <0.00195% CI: [2.01, 7.15]Regression, Cox
p-value: <0.00195% CI: [2.23, 8.36]Regression, Cox
Secondary
uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25
Urinary N-telopeptide (uNTX) corrected by creatinine \< 50 nmol/mmol at week 25.
Time frame: 25 weeks
Population: All participants who are randomized to the treatment phase, receive at least one dose of treatment phase investigational product, and have treatment phase baseline measurements of uNTx and at least one treatment phase post-baseline measurement of uNTx.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisphosphonate IV Q4W | uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25 | 13 Participants |
| Denosumab 180 mg Q12W | uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25 | 21 Participants |
| Denosumab 180 mg Q4W | uNTx (Corrected by Creatinine) < 50 Nmol/mmol at Week 25 | 23 Participants |
95% CI: [46.2, 79.2]
95% CI: [45.1, 79.6]
95% CI: [21.5, 55.1]