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

Sponsor

University Health Network, Toronto (Other)

Overall Status

Completed

CT.gov ID

NCT03520231

Collaborator

Amgen (Industry)

Enrollment

Location

Arms

26.9

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Carcinoma Kidney Cancer Ureter Cancer Bladder Cancer	Drug: Denosumab Other: Denosumab Placebo Drug: Gemcitabine Drug: Carboplatin Drug: Cisplatin Dietary Supplement: Calcium Dietary Supplement: Vitamin D	Phase 2

Detailed Description

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 Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 4, 2018

Actual Primary Completion Date :

Dec 1, 2020

Actual Study Completion Date :

Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denosumab and Standard Chemotherapy 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.	Drug: Denosumab RANK Ligand Inhibitor Other Names: XGEVA Drug: Gemcitabine Antineoplastic Agent Drug: Carboplatin Antineoplastic Agent Drug: Cisplatin Antineoplastic Agent Dietary Supplement: Calcium Calcium Supplement Dietary Supplement: Vitamin D Vitamin D Supplement
Placebo Comparator: Denosumab Placebo and Standard Chemotherapy 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.	Other: Denosumab Placebo Placebo Drug: Gemcitabine Antineoplastic Agent Drug: Carboplatin Antineoplastic Agent Drug: Cisplatin Antineoplastic Agent Dietary Supplement: Calcium Calcium Supplement Dietary Supplement: Vitamin D Vitamin D Supplement

Arm

Intervention/Treatment

Experimental: Denosumab and Standard Chemotherapy

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.

Drug: Denosumab

RANK Ligand Inhibitor

Other Names:

XGEVA

Drug: Gemcitabine

Antineoplastic Agent

Drug: Carboplatin

Antineoplastic Agent

Drug: Cisplatin

Antineoplastic Agent

Dietary Supplement: Calcium

Calcium Supplement

Dietary Supplement: Vitamin D

Vitamin D Supplement

Placebo Comparator: Denosumab Placebo and Standard Chemotherapy

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.

Other: Denosumab Placebo

Placebo

Drug: Gemcitabine

Antineoplastic Agent

Drug: Carboplatin

Antineoplastic Agent

Drug: Cisplatin

Antineoplastic Agent

Dietary Supplement: Calcium

Calcium Supplement

Dietary Supplement: Vitamin D

Vitamin D Supplement

Outcome Measures

Primary Outcome Measures

Difference in mean percentage change in serum c-telopeptide (sCTX) between the two arms (investigational drug arm and placebo arm). [Baseline to Week 10]
Mean percentage change should be greater than or equal to 30%.

Secondary Outcome Measures

Number of patients with a change in sCTx [Baseline to Week 10]
To determine the proportion of patients with a change in sCTx of >30% from baseline at week 1 to week 10
Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the investigational arm [Baseline to Week 10]
Mean percentage change in urinary N-telopeptide (uNTx) levels in the investigational arm [Baseline to Week 10]
Mean percentage change in sCTx levels in the investigational arm [Baseline to End of Chemotherapy (Week 20)]
Mean percentage change in bALP levels in the investigational arm [Baseline to End of Chemotherapy (Week 20)]
Mean percentage change in uNTx levels in the investigational arm [Baseline to End of Chemotherapy (Week 20)]
Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the placebo arm. [Baseline to Week 10]
Mean percentage change in urinary N-telopeptide (uNTx) levels in the placebo arm. [Baseline to Week 10]
Mean percentage change in sCTx levels in the levels in the placebo arm. [Baseline to End of Chemotherapy (Week 20)]
Mean percentage change in bALP levels in the levels in the placebo arm. [Baseline to End of Chemotherapy (Week 20)]
Mean percentage change in uNTx levels in the levels in the placebo arm. [Baseline to End of Chemotherapy (Week 20)]
Time to first on study symptomatic skeletal related events [2 years]
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
Progression free survival rate [1 year]
To determine progression free survival (PFS) in each arm at 1 year (with appropriate censoring) after last dose of chemotherapy
Progression free survival rate [18 months]
To determine progression free survival (PFS) in each arm at 18 months (with appropriate censoring) after last dose of chemotherapy
Overall survival rate [1 year]
To determine overall survival (OS) rate at 1 year (with appropriate censoring) after last dose of chemotherapy
Overall survival rate [18 months]
To determine overall survival (OS) rate at 18 months (with appropriate censoring) after last dose of chemotherapy
Number of participants with side effects in the investigational drug arm [2 years]
To evaluate safety and tolerability
Number of participants with side effects in the placebo arm [2 years]
To evaluate safety and tolerability

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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