This is a randomized, double-blind, double-dummy study designed to provide bridging data in an Asian population to Amgen's studies of denosumab in subjects with bone metastases from solid tumors. The study is designed to provide data to a large global dataset of phase-III studies including breast cancer, prostate cancer, and all solid tumors, plus multiple myeloma, to support the regulatory approval for marketing and patient access to denosumab for the prevention of SREs in Chinese subjects with bone metastases from solid tumors. The primary objective of this study is to evaluate and compare the percent change from baseline to Week 13 in the bone marker urinary amino-terminal cross-linking telopeptide of type I collagen (uNTx) corrected for urine creatinine (uNTx/uCr) in subjects treated with denosumab to those treated with zoledronic acid. The study is designed to test the superiority of denosumab over zoledronic acid.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
487
Denosumab will be given as a SC injection of 120 mg by administering a 1.7 mL volume in a single injection
Zoledronic acid 4 mg (or equivalent clearance-adjusted dose in subjects with baseline creatinine clearance \<=60 ml/min) will be diluted in either 0.9% sodium chloride or 5% dextrose injection and administered IV.
The placebo will consist of 1.7 mL 0.9% w/v sodium chloride
The placebo will consist of either 0.9% w/v sodium chloride or 5% dextrose injection
Subjects are strongly recommended to take daily supplements of at least 500 mg calcium from the day of consent and until completion of the Week 73 follow-up visit.
Subjects are strongly recommended to take daily supplements of at least 400 IU of vitamin D from the day of consent and until completion of the Week 73 follow-up visit.
GSK Investigational Site
Guangzhou, Guangdong, China
GSK Investigational Site
Guangzhou, Guangdong, China
GSK Investigational Site
Guangzhou, Guangdong, China
GSK Investigational Site
Wuhan, Hubei, China
GSK Investigational Site
Nanjing, Jiangsu, China
GSK Investigational Site
Nanjing, Jiangsu, China
GSK Investigational Site
Changchun, Jilin, China
GSK Investigational Site
Chengdu, Sichuan, China
GSK Investigational Site
Hangzhou, Zhejiang, China
GSK Investigational Site
Beijing, China
...and 15 more locations
Percent Change (Chg) From Baseline (BL) to Week (Wk)13 in Urinary Amino-terminal Cross-linking Telopeptide of Type I Collagen Corrected for Urine Creatinine (uNTx/uCr)
uNTx/uCr is the bone turnover marker correlated with the presence and extent of metastases, and the prognosis and response to bone targeted treatment (trt). uNTx/uCr was expressed in nanomoles bone collagen equivalent per millimole (nM BCE/mM). Primary objective: to compare the effect of denosumab with that of zoledronic acid on % chg from BL in uNTx/uCr at Wk 13 in par. of Asian ancestry with bone metastases from solid tumors. BL value is the most recent, non-missing value prior to or on the 1st study trt dose date. Chg from BL is the value at Wk13 minus BL value. Percent chg from BL is the chg from BL / BL value \* 100. For missing Wk 13 observations, the last post-BL value was carried forward to obtain the Wk 13 value.
Time frame: Baseline (BL) and Week (Wk) 13
Percentage Change From Baseline to Week 13 in Urinary Amino-terminal Cross-linking Telopeptide of Type I Collagen of Type I Collagen Corrected for Urine Creatinine (uNTx/uCr) in Chinese Participants.
uNTx/uCr is the bone turnover marker correlated with the presence and extent of metastases, and the prognosis and response to bone targeted treatment. uNTx/uCr was expressed in nanomoles bone collagen equivalent per millimole (nM BCE/mM). Secondary objective: to compare the effect of denosumab with that of zoledronic acid on % chg from BL in uNTx/uCr at Wk 13 in par. of Chinese ancestry with bone metastases from solid tumors. Baseline value is the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is the value at Week 13 minus Baseline value. Percent chg from BL is the chg from BL / BL value \* 100. For missing Wk 13 observations, the last post-BL value was carried forward to obtain the Wk 13 value.
Time frame: Baseline and Week 13
Percentage Change From Baseline to Week 13 in Urinary Amino-terminal Cross-linking Telopeptide of Type I Collagen of Type I Collagen Corrected for Urine Creatinine (uNTx/uCr) in Participants With Advanced Breast Cancer.
uNTx/uCr is the bone turnover marker correlated with the presence and extent of metastases, and the prognosis and response to bone targeted treatment. uNTx/uCr was expressed in nanomoles bone collagen equivalent per millimole (nM BCE/mM). Secondary objective: to compare the effect of denosumab with that of zoledronic acid on % chg from BL in uNTx/uCr at Wk 13 in breast cancer par. with bone metastases from solid tumors. Baseline value is the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is the value at Week 13 minus Baseline value. Percent chg from BL is the chg from BL / BL value \* 100. For missing Wk 13 observations, the last post-BL value was carried forward to obtain the Wk 13 value.
Time frame: Baseline and Week 13
Percent Change From Baseline in the Serum Bone-specific Alkaline Phosphatase (s-BALP) at Week 13.
Baseline value is the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is the value at Indicated visit minus Baseline value. Percent change from Baseline is the change from Baseline divided by Baseline value multiplied by 100.
Time frame: Baseline and Week 13
Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (Non-fatal Serious Adverse Events and Fatal Serious Adverse Events)
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or other events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the outcome listed above, liver injury and impaired liver function and grade 4 laboratory abnormalities. Number of participants with any AEs, non-fatal SAEs, fatal SAEs have been presented.
Time frame: From start of IP through the Study Phase (49 weeks post-dose) (assessed up to 73 weeks)
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade.
Clinical chemistry parameters were measured at the Screening and Weeks 2, 5, 9, 13, 25, 37, and 53 visits. Clinical chemistry parameters measured on-study included albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, calcium (Ca), creatinine, magnesium, and phosphorous (P) inorganic. All reported values are of participants with worst-case on-therapy increase to the specified grade: Any increase, that is, worst-case increase to grade 1, 2, 3, or 4 (any grade); worst-case increase to grade 3 (WC G3); and worst-case increase to grade 4 (WC G4). The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) was used for grading. Participants with missing Baseline grade were assumed to have a Baseline grade of 0. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.
Time frame: Baseline and up to last study-related visit (up to 53 weeks)
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade.
Hematology parameters included hemoglobin, lymphocytes, platelet count, total neutrophils, white blood cell (WBC) count. All reported values are of participants with worst-case on-therapy increase to the specified grade: Any increase, that is, worst-case increase to grade 1, 2, 3, or 4 (any grade); worst-case increase to grade 3 (WC G3); and worst-case increase to grade 4 (WC G4). Participants with missing Baseline grade were assumed to have a Baseline grade of 0. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.
Time frame: Baseline and up to last study-related visit (up to 53 weeks)
Number of Participants With Confirmed Anti-denosumab Antibody Formation at Day 1, Week 25 and Week 53.
Anti-denosumab antibody formation was assessed at Day 1, Week 25 and Week 53. Binding antibody assay was used to assess number of participants with anti-denosumab antibody.
Time frame: Day 1, Week 25 and Week 53
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49
Blood samples were drawn on study Day 1, pre-dose; 4 hours, 24 hours, and at Week 2 (168 hours); then pre-dose at Week 5, Week 9, Week 13, Week 17, Week 19 (no dose), Week 21, Week 25, and Week 49.
Time frame: Samples were collected at pre-dose (Day 1); 4 hours, 24 hours, 168 hours post-dose; pre-dose at Week 5, Week 9, Week 13, Week 17; Week 19 (at 336 hours); pre-dose at Week 21, Week 25, Week 49
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