A Study to Compare Denosumab With Zoledronic Acid in Subjects With Bone Metastases From Solid Tumors
Condition: Fractures, Bone
MeSH terms: Neoplasm Metastasis; Fractures, Bone
Intervention: Denosumab 70 mg/mL; Zoledronic acid 4 mg; Placebo IV; Placebo SC; Calcium supplement; Vitamin D supplement
Intervention description: 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.
Intervention MeSH terms: Vitamin D; Zoledronic Acid; Denosumab; Calcium
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 487.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GSK2371746; Denosumab; China; skeletal-related events; bone metastases; bridging study; solid tumors

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.
    

Eligibility 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).