search
Back to results

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

Primary Purpose

Urothelial Carcinoma, Kidney Cancer, Ureter Cancer

Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Denosumab
Denosumab Placebo
Gemcitabine
Carboplatin
Cisplatin
Calcium
Vitamin D
Sponsored by
University Health Network, Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Urothelial Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Princess Margaret Cancer Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Denosumab and Standard Chemotherapy

Denosumab Placebo and Standard Chemotherapy

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Number of patients with a change in sCTx
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
Mean percentage change in urinary N-telopeptide (uNTx) levels in the investigational arm
Mean percentage change in sCTx levels in the investigational arm
Mean percentage change in bALP levels in the investigational arm
Mean percentage change in uNTx levels in the investigational arm
Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the placebo arm.
Mean percentage change in urinary N-telopeptide (uNTx) levels in the placebo arm.
Mean percentage change in sCTx levels in the levels in the placebo arm.
Mean percentage change in bALP levels in the levels in the placebo arm.
Mean percentage change in uNTx levels in the levels in the placebo arm.
Time to first on study symptomatic skeletal related events
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
To determine progression free survival (PFS) in each arm at 1 year (with appropriate censoring) after last dose of chemotherapy
Progression free survival rate
To determine progression free survival (PFS) in each arm at 18 months (with appropriate censoring) after last dose of chemotherapy
Overall survival rate
To determine overall survival (OS) rate at 1 year (with appropriate censoring) after last dose of chemotherapy
Overall survival rate
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
To evaluate safety and tolerability
Number of participants with side effects in the placebo arm
To evaluate safety and tolerability

Full Information

First Posted
April 27, 2018
Last Updated
November 22, 2021
Sponsor
University Health Network, Toronto
Collaborators
Amgen
search

1. Study Identification

Unique Protocol Identification Number
NCT03520231
Brief Title
Study Comparing Denosumab With Standard Treatment in Urothelial Cancer Patients With Bone Metastases
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
September 4, 2018 (Actual)
Primary Completion Date
December 1, 2020 (Actual)
Study Completion Date
December 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Health Network, Toronto
Collaborators
Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urothelial Carcinoma, Kidney Cancer, Ureter Cancer, Bladder Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Denosumab and Standard Chemotherapy
Arm Type
Experimental
Arm Description
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.
Arm Title
Denosumab Placebo and Standard Chemotherapy
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Denosumab
Other Intervention Name(s)
XGEVA
Intervention Description
RANK Ligand Inhibitor
Intervention Type
Other
Intervention Name(s)
Denosumab Placebo
Intervention Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Gemcitabine
Intervention Description
Antineoplastic Agent
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Intervention Description
Antineoplastic Agent
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Description
Antineoplastic Agent
Intervention Type
Dietary Supplement
Intervention Name(s)
Calcium
Intervention Description
Calcium Supplement
Intervention Type
Dietary Supplement
Intervention Name(s)
Vitamin D
Intervention Description
Vitamin D Supplement
Primary Outcome Measure Information:
Title
Difference in mean percentage change in serum c-telopeptide (sCTX) between the two arms (investigational drug arm and placebo arm).
Description
Mean percentage change should be greater than or equal to 30%.
Time Frame
Baseline to Week 10
Secondary Outcome Measure Information:
Title
Number of patients with a change in sCTx
Description
To determine the proportion of patients with a change in sCTx of >30% from baseline at week 1 to week 10
Time Frame
Baseline to Week 10
Title
Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the investigational arm
Time Frame
Baseline to Week 10
Title
Mean percentage change in urinary N-telopeptide (uNTx) levels in the investigational arm
Time Frame
Baseline to Week 10
Title
Mean percentage change in sCTx levels in the investigational arm
Time Frame
Baseline to End of Chemotherapy (Week 20)
Title
Mean percentage change in bALP levels in the investigational arm
Time Frame
Baseline to End of Chemotherapy (Week 20)
Title
Mean percentage change in uNTx levels in the investigational arm
Time Frame
Baseline to End of Chemotherapy (Week 20)
Title
Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the placebo arm.
Time Frame
Baseline to Week 10
Title
Mean percentage change in urinary N-telopeptide (uNTx) levels in the placebo arm.
Time Frame
Baseline to Week 10
Title
Mean percentage change in sCTx levels in the levels in the placebo arm.
Time Frame
Baseline to End of Chemotherapy (Week 20)
Title
Mean percentage change in bALP levels in the levels in the placebo arm.
Time Frame
Baseline to End of Chemotherapy (Week 20)
Title
Mean percentage change in uNTx levels in the levels in the placebo arm.
Time Frame
Baseline to End of Chemotherapy (Week 20)
Title
Time to first on study symptomatic skeletal related events
Description
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
Time Frame
2 years
Title
Progression free survival rate
Description
To determine progression free survival (PFS) in each arm at 1 year (with appropriate censoring) after last dose of chemotherapy
Time Frame
1 year
Title
Progression free survival rate
Description
To determine progression free survival (PFS) in each arm at 18 months (with appropriate censoring) after last dose of chemotherapy
Time Frame
18 months
Title
Overall survival rate
Description
To determine overall survival (OS) rate at 1 year (with appropriate censoring) after last dose of chemotherapy
Time Frame
1 year
Title
Overall survival rate
Description
To determine overall survival (OS) rate at 18 months (with appropriate censoring) after last dose of chemotherapy
Time Frame
18 months
Title
Number of participants with side effects in the investigational drug arm
Description
To evaluate safety and tolerability
Time Frame
2 years
Title
Number of participants with side effects in the placebo arm
Description
To evaluate safety and tolerability
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Srikala Sridhar, M.D.
Organizational Affiliation
Princess Margaret Cancer Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs