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

NCT01920568 | Completed Phase 3 Results

• 1 other identifier: 114273
• Study Type: interventional
• Target: 487
• Locations: 3 countries
• Sites: 25

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.

Conditions

Fractures, Bone

Keywords

GSK2371746; Denosumab; China; skeletal-related events; bone metastases; bridging study; solid tumors

Outcome Measures

Primary Outcomes (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)

  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.

  Baseline (BL) and Week (Wk) 13

Secondary Outcomes (8)

• 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.

  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.

  Baseline and Week 13

• Percent Change From Baseline in the Serum Bone-specific Alkaline Phosphatase (s-BALP) at Week 13.

  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)

  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.

  Baseline and up to last study-related visit (up to 53 weeks)

Study Arms (2)

Denosumab 120 mg

EXPERIMENTAL

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; Drug: Placebo IV; Dietary Supplement: Calcium supplement; Dietary Supplement: Vitamin D supplement

Zoledronic acid 4 mg

EXPERIMENTAL

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; Drug: Placebo SC; Dietary Supplement: Calcium supplement; Dietary Supplement: Vitamin D supplement

Interventions

Denosumab 70 mg/mL BIOLOGICAL

Denosumab will be given as a SC injection of 120 mg by administering a 1.7 mL volume in a single injection

Denosumab 120 mg

Zoledronic acid 4 mg DRUG

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.

Zoledronic acid 4 mg

Placebo IV DRUG

The placebo will consist of 1.7 mL 0.9% w/v sodium chloride

Denosumab 120 mg

Placebo SC DRUG

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

Zoledronic acid 4 mg

Calcium supplement DIETARY_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.

Denosumab 120 mg; Zoledronic acid 4 mg

Vitamin D supplement DIETARY_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.

Denosumab 120 mg; Zoledronic acid 4 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Amgen: collaborator

Study Sites (25)

GSK Investigational Site

Guangzhou, Guangdong, 510060, China

Location

GSK Investigational Site

Guangzhou, Guangdong, 510120, China

Location

GSK Investigational Site

Guangzhou, Guangdong, 510515, China

Location

GSK Investigational Site

Wuhan, Hubei, 430030, China

Location

GSK Investigational Site

Nanjing, Jiangsu, 210002, China

Location

GSK Investigational Site

Nanjing, Jiangsu, 210009, China

Location

GSK Investigational Site

Changchun, Jilin, 130012, China

Location

GSK Investigational Site

Chengdu, Sichuan, 610041, China

Location

GSK Investigational Site

Hangzhou, Zhejiang, 310003, China

Location

GSK Investigational Site

Beijing, 100021, China

Location

GSK Investigational Site

Beijing, 100034, China

Location

GSK Investigational Site

Beijing, 100036, China

Location

GSK Investigational Site

Beijing, 100071, China

Location

GSK Investigational Site

Fuzhou, 350001, China

Location

GSK Investigational Site

Hangzhou, 310016, China

Location

GSK Investigational Site

Harbin, China

Location

GSK Investigational Site

Shanghai, 200025, China

Location

GSK Investigational Site

Shanghai, 200032, China

Location

GSK Investigational Site

Shanghai, 200070, China

Location

GSK Investigational Site

Shanghai, 200080, China

Location

GSK Investigational Site

Shanghai, 200233, China

Location

GSK Investigational Site

Tianjin, 300060, China

Location

GSK Investigational Site

Singapore, 119074, Singapore

Location

GSK Investigational Site

Taichung, 404, Taiwan

Location

GSK Investigational Site

Taoyuan District, 333, Taiwan

Location

MeSH Terms

Conditions

Fractures, Bone

Interventions

Denosumab; Zoledronic Acid

Condition Hierarchy (Ancestors)

Wounds and Injuries

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 8, 2013
• First Posted: August 12, 2013
• Study Start: August 1, 2013
• Primary Completion: February 1, 2015
• Study Completion: April 1, 2016
• Last Updated: January 16, 2017
• Results First Posted: August 25, 2016

Record last verified: 2016-07

Locations

TW (2); CN (22); SG (1)