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出境医 / 临床实验 / Study Comparing Denosumab With Standard Treatment in Urothelial Cancer Patients With Bone Metastases
Study Comparing Denosumab With Standard Treatment in Urothelial Cancer Patients With Bone Metastases
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 (Clinical Trial) |
| Estimated Enrollment : | 50 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 : | September 4, 2018 |
| Estimated Primary Completion Date : | December 1, 2020 |
| Estimated Study Completion Date : | December 2021 |
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 Name: 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
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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). [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to Week 10 ]
- Mean percentage change in urinary N-telopeptide (uNTx) levels in the investigational arm [ Time Frame: Baseline to Week 10 ]
- Mean percentage change in sCTx levels in the investigational arm [ Time Frame: Baseline to End of Chemotherapy (Week 20) ]
- Mean percentage change in bALP levels in the investigational arm [ Time Frame: Baseline to End of Chemotherapy (Week 20) ]
- Mean percentage change in uNTx levels in the investigational arm [ Time Frame: Baseline to End of Chemotherapy (Week 20) ]
- Mean percentage change in serum bone-specific alkaline phosphatase (bALP) in the placebo arm. [ Time Frame: Baseline to Week 10 ]
- Mean percentage change in urinary N-telopeptide (uNTx) levels in the placebo arm. [ Time Frame: Baseline to Week 10 ]
- Mean percentage change in sCTx levels in the levels in the placebo arm. [ Time Frame: Baseline to End of Chemotherapy (Week 20) ]
- Mean percentage change in bALP levels in the levels in the placebo arm. [ Time Frame: Baseline to End of Chemotherapy (Week 20) ]
- Mean percentage change in uNTx levels in the levels in the placebo arm. [ Time Frame: Baseline to End of Chemotherapy (Week 20) ]
- Time to first on study symptomatic skeletal related events [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 1 year ]To determine overall survival (OS) rate at 1 year (with appropriate censoring) after last dose of chemotherapy
- Overall survival rate [ Time Frame: 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 [ Time Frame: 2 years ]To evaluate safety and tolerability
- Number of participants with side effects in the placebo arm [ Time Frame: 2 years ]To evaluate safety and tolerability
Eligibility Criteria
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations
Locations
| Canada, Ontario | |
| Princess Margaret Cancer Centre | |
| Toronto, Ontario, Canada, M5G 2M9 | |
Sponsors and Collaborators
University Health Network, Toronto
Amgen
Investigators
| Principal Investigator: | Srikala Sridhar, M.D. | Princess Margaret Cancer Centre |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | April 27, 2018 | ||||
| First Posted Date ICMJE | May 9, 2018 | ||||
| Last Update Posted Date | September 29, 2020 | ||||
| Actual Study Start Date ICMJE | September 4, 2018 | ||||
| Estimated Primary Completion Date | December 1, 2020 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
Difference in mean percentage change in serum c-telopeptide (sCTX) between the two arms (investigational drug arm and placebo arm). [ Time Frame: Baseline to Week 10 ] Mean percentage change should be greater than or equal to 30%.
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE |
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| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Study Comparing Denosumab With Standard Treatment in Urothelial Cancer Patients With Bone Metastases | ||||
| Official Title ICMJE | 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 | ||||
| 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. |
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| 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 Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 2 | ||||
| Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double (Participant, Investigator) Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Active, not recruiting | ||||
| Estimated Enrollment ICMJE |
50 | ||||
| Original Estimated Enrollment ICMJE | Same as current | ||||
| Estimated Study Completion Date ICMJE | December 2021 | ||||
| Estimated Primary Completion Date | December 1, 2020 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | Canada | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT03520231 | ||||
| Other Study ID Numbers ICMJE | DENIM | ||||
| Has Data Monitoring Committee | Yes | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | University Health Network, Toronto | ||||
| Study Sponsor ICMJE | University Health Network, Toronto | ||||
| Collaborators ICMJE | Amgen | ||||
| Investigators ICMJE |
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| PRS Account | University Health Network, Toronto | ||||
| Verification Date | September 2020 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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