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A Study to Compare Denosumab With Zoledronic Acid in Subjects With Bone Metastases From Solid Tumors

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ClinicalTrials.gov Identifier: NCT01920568
Recruitment Status : Completed
First Posted : August 12, 2013
Results First Posted : August 25, 2016
Last Update Posted : January 16, 2017
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Fractures, Bone Biological: Denosumab 70 mg/mL Drug: Zoledronic acid 4 mg Drug: Placebo IV Drug: Placebo SC Dietary Supplement: Calcium supplement Dietary Supplement: Vitamin D supplement Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 487 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: DCA114273: A Study Comparing Denosumab With Zoledronic Acid in Subjects of Asian Ancestry With Bone Metastases From Solid Tumors
Study Start Date : August 2013
Actual Primary Completion Date : February 2015
Actual Study Completion Date : April 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Denosumab 120 mg
Subjects will be administered with Denosumab 120 mg subcutaneous (SC) injection for a maximum of 13 doses and placebo IV infusion over >=15 minutes once every 4 weeks.
Biological: Denosumab 70 mg/mL
Denosumab will be given as a SC injection of 120 mg by administering a 1.7 mL volume in a single injection

Drug: Placebo IV
The placebo will consist of 1.7 mL 0.9% w/v sodium chloride

Dietary Supplement: Calcium supplement
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.

Dietary Supplement: Vitamin D supplement
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.

Experimental: Zoledronic acid 4 mg
Subjects will be administered with Zoledronic acid 4 mg IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo SC once every 4 weeks.
Drug: Zoledronic acid 4 mg
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.

Drug: Placebo SC
The placebo will consist of either 0.9% w/v sodium chloride or 5% dextrose injection

Dietary Supplement: Calcium supplement
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.

Dietary Supplement: Vitamin D supplement
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.




Primary Outcome Measures :
  1. 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) [ Time Frame: Baseline (BL) and Week (Wk) 13 ]
    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.


Secondary Outcome Measures :
  1. 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. [ Time Frame: Baseline and Week 13 ]
    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.

  2. 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. [ Time Frame: Baseline and Week 13 ]
    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.

  3. Percent Change From Baseline in the Serum Bone-specific Alkaline Phosphatase (s-BALP) at Week 13. [ Time Frame: Baseline and 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.

  4. Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (Non-fatal Serious Adverse Events and Fatal Serious Adverse Events) [ Time Frame: From start of IP through the Study Phase (49 weeks post-dose) (assessed up to 73 weeks) ]
    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.

  5. Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. [ Time Frame: Baseline and up to last study-related visit (up to 53 weeks) ]
    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.

  6. Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. [ Time Frame: Baseline and up to last study-related visit (up to 53 weeks) ]
    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.

  7. Number of Participants With Confirmed Anti-denosumab Antibody Formation at Day 1, Week 25 and Week 53. [ Time Frame: 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.

  8. 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 [ 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 ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject understands the nature and purpose of this study and the study procedures, which have been explained by the Investigator or delegate, and subject has signed the written informed consent for the overall study. The subject must sign a separate written informed consent to be eligible for enrolment in the pharmacokinetic substudy.
  • Adult (aged >=18 years) of Asian ancestry with a histologically or cytologically confirmed solid tumor. In addition, subjects who are enrolled at a center in mainland China or at an SFDA-certified center in Hong Kong including the approximately 33 subjects in the pharmacokinetic substudy must be of Chinese race, ancestry, or heritage. Subjects enrolled in other regions or countries, such as Taiwan and Singapore, or at a non-SFDA-certified center in Hong Kong, are not required to be of Chinese race or ancestry.
  • Current or prior documented radiographic evidence (i.e., x-ray, computer tomography [CT], or magnetic resonance imaging [MRI]) of at least 1 bone metastasis.
  • Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined below, during the study and for 6 months after end of study treatment. Women who report having a pregnancy during this study will be followed for birth outcomes. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: An intrauterine device or intrauterine system with a documented failure rate of less than 1% per year; Male partner sterilization prior to the female subject's enrollment and the male is the sole sexual partner for that subject; the information on the male sterility can come from the site personnel's review of subject's medical records; medical examination of the subject and/or semen analysis; or interview with the subject on his medical history; complete abstinence from sexual intercourse for 14 days prior to first dose of study treatment, through the dosing period, and for at least 7 months after the last dose of study treatment; double-barrier contraception: male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository); implants of levonorgestrel or etonogestrel where not contraindicated for this patient population or per local practice; injectable progesterone where not contraindicated for this patient population or per local practice; percutaneous contraceptive patches where not contraindicated for this patient population or per local practice; Oral contraceptives (either combined or progesterone only) where not contraindicated for this patient population or per local practice. Females of child bearing potential who do not have male partners as part of their preferred and usual lifestyle are not required to use contraception.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (refer protocol for details).
  • Adequate baseline organ function as defined by the following criteria: Serum aspartate aminotransferase (AST) <=2.0 x upper limit of normal (ULN); Serum alanine aminotransferase (ALT) <=2.0 x ULN; Serum total bilirubin <=1.0 x ULN; creatinine clearance (calculated using the Cockcroft-Gault formula) >=30 milliliter per minute (mL/min); serum calcium or albumin-adjusted serum calcium >=2.0 millimole per liter (mmol/L) (8.0 mg/dL) and <=2.9 mmol/L (11.5 miligram per deciliter [mg/dL]). Subjects must not have taken supplemental calcium for at least 8 hours prior to collection of the blood sample for screening serum calcium determination.
  • Life expectancy of at least 6 months, in the opinion of the Investigator.

Exclusion Criteria:

  • Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that, in the opinion of the Investigator, could interfere with subject's safety, obtaining informed consent or compliance to the study procedures; The Investigator should consult the GSK Medical Monitor prior to enrolling a subject if s/he is unsure if a condition might interfere with the subject's safety or participation in this study.
  • Any prior treatment with intravenous (IV) or oral bisphosphonates.
  • Prior treatment with denosumab.
  • Planned radiation therapy or surgery to bone.
  • Known brain metastases.
  • Prior history or current evidence of osteomyelitis or osteonecrosis of the jaws (ONJ), an active dental or jaw condition that requires oral surgery, non-healed dental or oral surgery, or planned invasive dental procedure over the course of the study.
  • Evidence of any of the following conditions per subject self report or medical chart review: any prior or current malignancy (other than the cancer under study in this protocol) with active disease within 3 years before randomization; unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); known infection with human immunodeficiency virus (HIV); active infection with hepatitis B or hepatitis C virus.
  • Pregnant women, women planning to become pregnant within 7 months after end of study treatment, and women who are breastfeeding. Women who are breast feeding should discontinue nursing prior to the first dose of study treatment and should refrain from nursing throughout the treatment period and for 7 months following their last dose of study treatment.
  • Male subjects unable or unwilling to use adequate contraception methods during the study and for 6 months after end of study treatment should be excluded.
  • Subject is currently enrolled in another investigational device or investigational product study, or has not completed at least 30 days, 5 half lives, or the duration of biological effect, whichever is longer, since ending such a study.
  • Known sensitivity to any of the investigational products or supplements to be administered during the study (i.e., zoledronic acid, mammalian derived products, calcium, or vitamin D).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01920568


Locations
China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510060
GSK Investigational Site
Guangzhou, Guangdong, China, 510120
GSK Investigational Site
Guangzhou, Guangdong, China, 510515
China, Hubei
GSK Investigational Site
Wuhan, Hubei, China, 430030
China, Jiangsu
GSK Investigational Site
Nanjing, Jiangsu, China, 210002
GSK Investigational Site
Nanjing, Jiangsu, China, 210009
China, Jilin
GSK Investigational Site
Changchun, Jilin, China, 130012
China, Sichuan
GSK Investigational Site
Chengdu, Sichuan, China, 610041
China, Zhejiang
GSK Investigational Site
Hangzhou, Zhejiang, China, 310003
China
GSK Investigational Site
Beijing, China, 100021
GSK Investigational Site
Beijing, China, 100034
GSK Investigational Site
Beijing, China, 100036
GSK Investigational Site
Beijing, China, 100071
GSK Investigational Site
Fuzhou, China, 350001
GSK Investigational Site
Hangzhou, China, 310016
GSK Investigational Site
Harbin, China
GSK Investigational Site
Shanghai, China, 200025
GSK Investigational Site
Shanghai, China, 200032
GSK Investigational Site
Shanghai, China, 200070
GSK Investigational Site
Shanghai, China, 200080
GSK Investigational Site
Shanghai, China, 200233
GSK Investigational Site
Tianjin, China, 300060
Singapore
GSK Investigational Site
Singapore, Singapore, 119074
Taiwan
GSK Investigational Site
Taichung, Taiwan, 404
GSK Investigational Site
Taoyuan, Taiwan, 333
Sponsors and Collaborators
GlaxoSmithKline
Amgen
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01920568     History of Changes
Other Study ID Numbers: 114273
First Posted: August 12, 2013    Key Record Dates
Results First Posted: August 25, 2016
Last Update Posted: January 16, 2017
Last Verified: July 2016

Keywords provided by GlaxoSmithKline:
GSK2371746
Denosumab
China
skeletal-related events
bone metastases
bridging study
solid tumors

Additional relevant MeSH terms:
Neoplasm Metastasis
Fractures, Bone
Neoplastic Processes
Neoplasms
Pathologic Processes
Wounds and Injuries
Vitamins
Vitamin D
Zoledronic acid
Diphosphonates
Denosumab
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents