A Placebo-controlled Phase II Study of Bone-targeted Radium-223 in Symptomatic Hormone-refractory Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of the investigational radioisotope Radium-223 in treatment of men with prostate cancer and bone metastases that no longer respond to hormonal treatment.

Detailed Description
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Primary objective: To study the biological effectiveness of radium-223 therapy measured as: Time to occurrence of skeletal-related events(SREs) Change in bone-specific alkaline phosphatase (bone-ALP) levels Secondary objectives: To study the efficacy of radium-223 therapy in terms of: Frequency of new SREs Proportions of patients with an SRE Proportions of patients with SRE at different time points Changes of biochemical markers of bone turnover Treatment response with regard to pain and analgesic use(termed Palliative effect in study protocol) Quality of life assessment Overall survival To study the safety of the repeated radium-223 regimen Total Enrollment:64 Study start: February 2004

Official Title
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A Phase II Randomised, Placebo-controlled, Multicentre Study in Prostate Cancer Patients With Painful Bone Metastases to Evaluate the Efficacy of Repeated Radium-223 Injections

Conditions
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Prostate Cancer, Neoplasm Metastasis

Intervention / Treatment
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* Drug: Radium-223 dichloride (BAY88-8223)
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically/cytologically confirmed adenocarcinoma of the prostate Patient has received or is receiving hormonal treatment (orchiectomy, polyoestradiol phosphate, or gonadotropin-releasing hormone analogue with or without antiandrogen) Metastatic disease with positive bone scan within 2 months before treatment with more than one cancer related lesion or with one painful cancer related lesion in the presence of increasing PSA levels as follows: PSA >5 ng/ml, with increases on at least 2 successive occasions at least 2 weeks apart. Patient is referred to local field radiotherapy (EBR) for metastatic bone pain. The area to be treated (index site) should match the positive bone scan, local radiation area not exceeding 400 cm2 ECOG performance status: 0-2 Life expectancy: at least 3 months Age more than 40 years Laboratory requirements: Hematology: Neutrophil count ≥1,5 x 109/L Platelet count at least ≥100 x109/L and stable Hemoglobin >100 g/l or 10 g/dL Hepatic function: Bilirubin within normal institutional limits ASAT and ALAT <2,5 times upper limit of normal (ULN) Renal function: Creatinine <1,5 times the ULN (i.e. NCI grade ≤1) Patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow-up visits and examinations Patient has been fully informed about the study and has signed the informed consent form Exclusion Criteria: Has received an investigational drug in the 4 weeks before or is scheduled to receiving one during the planned treatment period Has received chemo-, immunotherapy or external radiotherapy within weeks before study drug administration Has started treatment with bisphosphonates within 3 months before administration of study drug. Has previously received systemic radiotherapy with strontium, samarium or rhenium Change in hormonal therapy within the last 6 weeks before study drug administration Other currently active (relapse within the last 3 year) malignancy (except nonmelanoma skin cancer) or known brain, liver, lung, visceral and lymphatic metastases dominating the clinical picture of the patient Has received blood transfusion within last month Other serious illness or medical condition as follows: any uncontrolled infection heart insufficiency, grade 3 or 4 as specified in NCI-CTC criteria grade 2 or greater motor or sensory neuropathy Crohn's disease or Ulcerative colitis 9) Known non-pathological bone fracture within the last two months

Ages Eligible for Study
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Minimum Age: 40 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride (Xofigo, BAY88-8223)<br>Each subject receives local filed external beam radiotherapy (EBR) and repeated injections of the investigational drug radium-223 (EBR+Radium-223) | Drug: Radium-223 dichloride (BAY88-8223)<br>* Four Radium-223 injections were given at 4-weekly intervals starting after the first fraction of EBR.<br>|
| Placebo Comparator: Saline<br>Each subject receives local filed external beam radiotherapy (EBR) and repeated injections of saline (EBR+placebo) | Drug: Saline<br>* Four Saline injections were given at 4-weekly intervals starting after the first fraction of EBR.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to occurrence of Skeletal-related Events (SRE) | SREs are defined as: Increase in pain severity index during the last week; Increase in analgesic consumption; Neurological symptoms secondary to skeletal manifestations of prostate cancer; New pathologic bone fractures (vertebral and non-vertebral); Tumour related orthopaedic surgical intervention; Subsequent external beam radiation to relieve skeletal pain; Use of radioisotopes to relieve new skeletal related symptoms; Use of corticosteroids for skeletal pain, at doses aimed for pain palliation; Use of chemotherapy, bisphosphonates, or hormones, for the treatment of skeletal disease progression | Up to 12 Month | 
| Relative change (%) in bone-ALP levels from baseline to 4 weeks after last injection |  | Up to 12 Month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of SREs per patient |  | Up to 12 Month | 
| Changes in the levels of biochemical markers of bone formation |  | Up to 12 Month | 
| Change in Prostate Specific Antigen (PSA) |  | Up to 12 Month | 
| Change in pain level |  | Up to 12 Month | 
| Changes in analgesic use during study period |  | Up to 12 Month | 
| Changes in Edmonton Symptom Assessment Scale (ESAS) from baseline |  | Up to 12 Month | 
| Overall survival |  | up to 24 months | 
| Adverse events |  | up to 24 months | 
| Clinical laboratory tests including haematology, renal and liver function parameters |  | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HRPC, Recurrent Prostate Cancer, Metastatic Cancer