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)
6
Enrollment
1
Location
2
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 DiseaseIntervention/TreatmentPhase
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

ArmIntervention/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

    1. 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

    1. 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

    2. Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the investigational arm [Baseline to Week 10]

    3. Mean percentage change in urinary N-telopeptide (uNTx) levels in the investigational arm [Baseline to Week 10]

    4. Mean percentage change in sCTx levels in the investigational arm [Baseline to End of Chemotherapy (Week 20)]

    5. Mean percentage change in bALP levels in the investigational arm [Baseline to End of Chemotherapy (Week 20)]

    6. Mean percentage change in uNTx levels in the investigational arm [Baseline to End of Chemotherapy (Week 20)]

    7. Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the placebo arm. [Baseline to Week 10]

    8. Mean percentage change in urinary N-telopeptide (uNTx) levels in the placebo arm. [Baseline to Week 10]

    9. Mean percentage change in sCTx levels in the levels in the placebo arm. [Baseline to End of Chemotherapy (Week 20)]

    10. Mean percentage change in bALP levels in the levels in the placebo arm. [Baseline to End of Chemotherapy (Week 20)]

    11. Mean percentage change in uNTx levels in the levels in the placebo arm. [Baseline to End of Chemotherapy (Week 20)]

    12. 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

    13. 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

    14. 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

    15. Overall survival rate [1 year]

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

    16. Overall survival rate [18 months]

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

    17. Number of participants with side effects in the investigational drug arm [2 years]

      To evaluate safety and tolerability

    18. 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:
    No
    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Princess Margaret Cancer CentreTorontoOntarioCanadaM5G 2M9

    Sponsors and Collaborators

    • University Health Network, Toronto
    • Amgen

    Investigators

    • Principal Investigator: Srikala Sridhar, M.D., Princess Margaret Cancer Centre

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University Health Network, Toronto
    ClinicalTrials.gov Identifier:
    NCT03520231
    Other Study ID Numbers:
    • DENIM
    First Posted:
    May 9, 2018
    Last Update Posted:
    Nov 23, 2021
    Last Verified:
    Sep 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 23, 2021