Rhenium-188-HEDP vs. Radium-223-chloride in Patients With Advanced Prostate Cancer Refractory to Hormonal Therapy

Study Overview
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Brief Summary
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Radium-223 chloride is an alpha-emitting radiopharmaceutical with proven survival benefit in patients with castration-resistant prostate cancer metastatic to bone. Beta-emitting radiopharmaceuticals have proven efficacy for palliating malignant bone pain. Nowadays, rhenium-188-HEDP is used in clinical practice for pain relief and palliative care. Several studies suggest that also rhenium-188-HEDP has the potential to improve overall survival. The purpose of this study is to investigate if treatment with rhenium-188-HEDP results in improvement of overall survival compared to treatment with radium-223-chloride.

Detailed Description
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The main objective of this trial is to compare rhenium-188-HEDP (a beta-emitting radiopharmaceutical) with radium-223-chloride (an alfa-emitting radiopharmaceutical), in patients with castration-resistant prostate cancer metastatic to bone, with overall survival as primary endpoint. For radium-223-chloride, an overall survival benefit has been proven in a large randomized phase III trial. Although such a trial has never been performed for rhenium-188-HEDP, some trials in literature suggest a survival benefit for rhenium as well. Rhenium has some advantages compared to radium. Firstly, it is easily available as it can be produced in the hospital. Secondly, the costs of rhenium are significantly lower compared to radium. Lastly, rhenium seems to have a favorable pain response. However, no randomized trials have been performed to confirm this.

Official Title
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Repeated Rhenium-188-HEDP Versus Radium-223-chloride in Patients With Metastatic Castration-resistant Prostate Cancer: The RaRe Study

Conditions
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Prostate Cancer Metastatic to Bone

Intervention / Treatment
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* Drug: Radium-223 chloride
* Drug: Rhenium-188-HEDP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, 18 years or older Histologically confirmed prostate cancer Bone metastases (≥ 6 lesions) showing pathological uptake at bone scintigraphy. WHO performance status of ≤2 Life expectancy of at least 6 months Castration-resistant disease: serum testosterone level of ≤ 1.7 nmol per liter (≤50 ng per deciliter) after bilateral orchiectomy or during maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist. During study treatment the maintenance androgen-deprivation therapy must be continued. Baseline PSA ≥5 ng/ml with evidence of progressively increasing PSA values Symptomatic disease with either regular use of analgesic medication or treatment with external-beam radiotherapy for cancer-related bone pain within the previous 12 weeks. Progression on or after treatment with docetaxel, or inability to receive docetaxel. Adequate renal function (serum creatinine level ≤1.5 x ULN) Adequate hematological function defined as absolute neutrophil count ≥ 1.5x10^9/L and platelet count ≥100x 10^9/L) Written informed consent Exclusion Criteria: Treatment with chemotherapy within the previous 4 weeks Continuation of treatment with abiraterone or enzalutamide Previous hemibody external radiotherapy Systemic radiotherapy with radioisotopes within the previous 24 weeks Malignant lymphadenopathy ≥3cm in the short-axis diameter Presence of visceral metastases Imminent of established spinal cord compression Active uncontrolled bacterial, viral or fungal infection History of another malignancy within the last five years except adequately treated basal cell carcinoma of the skin Organ allografts requiring immunosuppressive therapy. Any serious uncontrolled concommitant disease Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule: those conditions should be discussed with the patient before registration in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized between radium-223-chloride intravenously, for a total of 6 administrations (every 4weeks) rhenium-188-HEDP intravenously for a total of 3 administratrions (every 8 weeks)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Radium-223-chloride<br>Radium-223-chloride 50kBg/kg, every 4 weeks intravenously, for a total of 6 administrations. | Drug: Radium-223 chloride<br>* Intravenously 50 kBq/kg every 4 weeks. Total: 6 administrations<br>* Other names: Radium-223 dichloride;|
| Experimental: Rhenium-188-HEDP<br>Rhenium-188-HEDP 40MBq/kg, every 8 weeks intravenously, for a total of 3 administrations. | Drug: Rhenium-188-HEDP<br>* Intravenously 40 MBq/kg every 8 weeks. Total: 3 administrations<br>* Other names: 188Rhenium-etidronate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time from randomization until death due to any cause, | Time from randomization until death due to any cause, an average of 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to PSA progression | Time from randomization to the date of a minimum of rising PSA levels with an interval of >1week between each determination | Time from randomization to the date of a minimum of rising PSA levels, an average of 8 months (PSA measured at baseline and every 4 weeks). | 
| Time to total-ALP progression | Time from randomization to the date of earliest objective evidence of ALP progression. | Time from randomization to the date of earliest objective evidence of ALP progression, an average of 8 months (ALP measure at baseline and every 4 weeks) | 
| Clinical progression | Time from randomization to the date of first clinical progression. | Time from randomization to the date of first clinical progression, an average of 12 months | 
| Time to first SRE | Time from randomization to the date of first skeletal related events | Time from randomization to the date of first skeletal related events, an average of 12 months | 
| Quality of life | Measured by the EORTC quality of Life Questionnaire C30 | Assessed through study completion, an average of 1 year | 
| Effect on pain | Measured with a visual analogue scale | Assessed through study completion, an average of 1 year | 
| Incremental Cost Effectiveness Ratio (IVER) | Ratio between the difference in costs and the difference in benefits (quality of life of treatment with rhenium-188-HEDP of radium-223-chloride) | Assessed through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone metastases, Rhenium-188-HEDP, Radium 223-chloride, Survival, Prostate cancer