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

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.

Inclusion Criteria:

• Histologically or cytologically confirmed urothelial carcinoma (kidney, ureter, bladder) with metastatic disease involving the bones, not amenable to curative treatment
• Mixed histologies permitted as long as urothelial histology is the major component Presence of one or more bone metastases
• No prior systemic chemotherapy for metastatic disease (immunotherapy permitted)
• Starting first line chemotherapy for metastatic urothelial cancer with gemcitabine and cisplatin or gemcitabine and carboplatin and planned to receive 4-6 cycles
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Adequate renal function
• Acceptable serum calcium or albumin-adjusted serum calcium
• Adequate hepatic function
• Patients all require oral examination and appropriate preventative dentistry prior to starting treatment
• Expected life expectancy of at least 3 months

Exclusion Criteria:

• Prior chemotherapy for metastatic disease
• Current or prior IV bisphosphonate or denosumab administration
• Current or prior oral bisphosphonate administration to treat bone metastases
• Unacceptable renal function
• Abnormal bone metabolism (Paget's disease)
• Untreated or symptomatic brain metastases
• Patients with a history of other malignancies, with exceptions
• Significant dental/oral disease
• Administration of other prior anticancer therapies within 2 weeks of randomization
• Patient is pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
• Female of child bearing potential is not willing to use, in combination with her partner, highly effective contraception during treatment and for 7 months after the end of treatment
• Known sensitivity to any of the products to be administered during the study
• History of any other clinically significant disorder, condition or disease that in the opinion of the investigator excludes the patient