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Denosumab

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Denosumab, given subcutaneously at a dose of 120 mg, every 4 weeks.

Gemcitabine, given intravenously at standard doses, on Days 1 and 8 of every 21 day cycle, for 3-4 cycles.

Carboplatin, given intravenously at standard doses, on Day 1 of every 21 day cycle, for 3-4 cycles.

OR Cisplatin, given intravenously at standard doses, on Day 1 of every 21 day cycle, for 3-4 cycles.

Calcium, orally at a dose of 1000 mg, once daily.

Vitamin D, orally at a dose of 400 IU, once daily.

Denosumab placebo, given subcutaneously, every 4 weeks.

Gemcitabine, given intravenously at standard doses, on Days 1 and 8 of every 21 day cycle, for 3-4 cycles.

Carboplatin, given intravenously at standard doses, on Day 1 of every 21 day cycle, for 3-4 cycles.

OR Cisplatin, given intravenously at standard doses, on Day 1 of every 21 day cycle, for 3-4 cycles.

Calcium, orally at a dose of 1000 mg, once daily.

Vitamin D, orally at a dose of 400 IU, once daily.

Denosumab Placebo

Srikala Sridhar, M.D.

This is a phase 2 study of the drug denosumab for the management bone metastases from urothelial cancer.

The purpose of this study is to find out how effective denosumab is in the management of bone metastases from urothelial cancer. This will be done by comparing denosumab with standard treatment, compared to placebo and standard treatment.

Denosumab is a monoclonal antibody that binds to a protein called Receptor Activator of Nuclear Factor κB (RANK). RANK works by telling certain cells called osteoclasts to break down bone tissue. The binding of denosumab to RANK stops it from telling osteoclasts to break down bone tissue which may help with symptoms related bone metastases from urothelial cancer.

This is a multicenter, randomized, double blind, Phase II study. Participants eligible for this study have metastatic urothelial cancer and bone metastases and are planned to receive 4-6 cycles of a standard of care platinum-doublet regimen. In a double blind manner, 50 participants will be randomized in a 1:1 ratio to receive denosumab 120 mg or matching placebo subcutaneously every 4 weeks with their first dose coinciding with the first cycle of chemotherapy. Patients will continue on denosumab/placebo even after all planned chemotherapy cycles have been delivered and until the end of the study at 18 months after the last dose of chemotherapy. Patients with symptomatic progression in the bone may be unblinded and crossed over to denosumab (if on placebo). All participants will be provided with 1000 mg of calcium and 400 IU of vitamin D to be taken daily. Participants who discontinue the investigational product early will be followed for disease status and survival.

Study Comparing Denosumab With Standard Treatment in Urothelial Cancer Patients With Bone Metastases

A Multicenter Randomized Double Blind Study Examining the Efficacy and Safety of Denosumab in Combination With First Line Platinum-based Chemotherapy for Patients With Bone Metastasis Secondary to Metastatic Urothelial Cancer

Mean percentage change should be greater than or equal to 30%.

To determine the proportion of patients with a change in sCTx of \>30% from baseline at week 1 to week 10

To determine and compare the time to first on study symptomatic skeletal related events (SSE); (fracture, surgery, radiation to bone, or spinal cord compression) between each arm of the study

To determine progression free survival (PFS) in each arm at 1 year (with appropriate censoring) after last dose of chemotherapy

To determine progression free survival (PFS) in each arm at 18 months (with appropriate censoring) after last dose of chemotherapy

To determine overall survival (OS) rate at 1 year (with appropriate censoring) after last dose of chemotherapy

To determine overall survival (OS) rate at 18 months (with appropriate censoring) after last dose of chemotherapy

Amgen

University Health Network, Toronto

Spots Global Cancer Trial Database for denosumab placebo