Efficacy and Safety of Systemic Treatments of Bone Metastases From Kidney Cancer in Patients Treated With Targeted Therapies

Study Overview
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Brief Summary
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Multicenter, randomized, open-label, 2-arm, parallel-group, phase III study whose goal is to assess the efficacy and safety profile of bone-targeted treatments (Arm A: denosumab or zoledronic acid) versus the control arm (Arm B: no specific treatment) in patients with bone metastases under targeted therapy for Metastatic Renal Cell Carcinoma.

Official Title
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Multicenter Randomized Phase III Study Evaluating the Efficacy and Safety of Systemic Treatments of Bone Metastases From Kidney Cancer in Patients Treated With Targeted Therapies

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: denosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Histologically proven mRCC. Administration of one of the systemic agents in use for the treatment of mRCC (no more than three prior systemic therapy regimens). Patients with at least 6 months of 1st line treatment and a bone event may be included. More than 1 bone metastasis. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2. Adequate renal function (serum creatinine ≤ 200 mmol/L or creatinine clearance ≥ 30 mL/min according to Cockroft formula or MDRD formula for patients older than 65 years). Covered by a medical insurance. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Signed informed consent. Accepting to use effective contraception during study treatment and within 5 months after final dose of study therapy. Exclusion Criteria: Prior bisphosphonate or denosumab treatment in the year before inclusion. Imminent or ongoing nerve or spinal compression as per the investigator's judgement. Ongoing first-line therapy, started for less than 6 months (patients with BM at time of metastases diagnosis will initially benefit from the angiogenesis targeted agents used and are not at higher risk). Anticancer treatment under investigation. Paraneoplastic hypercalcemia (corrected total calcium > 2.7 mmol/L). Grade 4 toxicity under previous targeted agents. Liver failure (AST and/or ALT ≥ 5.0 x upper limit of normal (ULN) or total bilirubin beyond normal limits). Severe hypocalcaemia > 2.8 mmol/l. Fructose intolerance. Invasive dental procedure (i.e. tooth extraction, dental implants, oral surgery) within the 10 days prior to randomization or required dental procedures at the pre-inclusion dental examination. Psychological, familial, sociological, geographical conditions that would limit compliance with study protocol requirements. Pregnant or breastfeeding woman. Females of child-bearing potential must have a negative serum pregnancy test within 7 days prior inclusion. Life expectancy ≤ 3 months. Participation to another clinical trial that might interfere with the evaluation of the main criterion. Known hypersensitivity to the active substance or to any of the excipients of bisphosphonate or denosumab.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>bone targeted treatment (denosumab or zoledronic acid) | Drug: denosumab<br>* Single subcutaneous injection of denosumab 120 mg every 4 weeks One intravenous infusion of zoledronic acid 4 mg every 4 weeks, according to labelled use.<br>* Other names: zoledronic acid;|
| No Intervention: Arm B<br>no specific treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first Skeletal Related Event | Defined as the time from randomization to first SRE. Patients without event will be censored at the time of the last clinical evaluation. | Up to 54 months after the first inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of specific event-free survivals | Specific times from randomization to appearance of the first Skeletal Related Event. | Up to 54 months after the first inclusion | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Incidence of adverse events (AEs) assessed using the National Cancer Institute - Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4 grading scale, specific registration of ONJ or other osteonecrosis and rate of skeletal event per patient during study duration | Every 3 months until the 18th month for each patient | 
| Evolution of pain severity | Proportion of patients with a clinically meaningful change in pain severity evaluated using a numerical rating scale (NRS) | Every 3 months until the 18th month for each patient | 
| Evolution of pain | Proportion of patients that shifted from not taking a strong opioid at baseline | Every 3 months until the 18th month for each patient | 
| Patient's condition evaluation | Functional Assessment of cancer Therapy-General (FACT-G) questionnaire, made of 27 items measuring the respondents' health state, each of which is answered using a five-point scale from 0 (not at all) to 4 (very much). Questions are phrased so that higher numbers indicate a better health state. Subscale scores are added to obtain total score. | Up to 9 months for each patient (evaluated at baseline, months 3, 6, 9) | 
| Patient's condition evaluation | EuroQoL 5 Dimensions 5 Levels questionnaire is a scale used in the health state description. Each items is a three-level scale : having no problems, having some or moderate problems, being unable to do/having extreme problems.The respondents are asked to choose one of the statements which best describes their health status of surveyed day. Rated level can be coded as a number 1, 2, or 3, which indicates having no problems for 1, having some problems for 2, and having extreme problems for 3. As a result, a person's health status can be defined by a 5-digit number, ranging from 11111 (having no problems in all dimensions) to 33333 (having extreme problems in all dimensions). | Up to 18 months for each patient (evaluated at baseline, months 3, 6, 9 and 18) | 
| Overall survival | Measured from the date of randomization to the date of death from any cause | Up to 54 months after the first inclusion | 
| Evaluation of the different practices for bone metastases treatments | Financial evaluation of centers' practices (home or hospitalization) | Up to 18 months for each patient | 
| Cost-utility analysis | All the hospitalization costs will be collected during the timeframe: outpatient, inpatient, and home care | Up to 18 months for each patient | 
| Cost-effectiveness analyses | All the hospitalization costs will be collected during the timeframe: outpatient, inpatient, and home care | Up to 18 months for each patient | 
| Budget impact analysis | Quantification of financial consequences of rolling out this kind of medical supportive care strategy throughout the health system. | Up to 18 months for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone Metastases