PK in Pts With HRPC & Skeletal Metastes

Study Overview
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Brief Summary
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Primary objective: To investigate the biodistribution, radiation dosimetry, and pharmacokinetics of two separate intravenous (IV) injections of Xofigo (100 kBq/kg body weight [b.w.] [=110 kBq/kg based on the 2015 National Institute of Standards and Technology standardization], 6 weeks apart). Secondary objectives: To determine the safety of IV injections of Xofigo after two separate injections (6 weeks apart), to evaluate treatment response (antitumour effect in osteoblastic bone metastases) of Xofigo treatment consisting of two injections of activity 100 kBq/kg b.w. (=110 kBq/kg based on the 2015 National Institute of Standards and Technology standardization), 6 weeks apart and to evaluate long term radiation toxicity and to collect survival data at 6 and 12 months after the first injection

Official Title
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A Phase I, Open-label, Dosimetry, Biodistribution and Pharmacokinetic Study of Alpharadin™ in Patients With Hormone Refractory Prostate Cancer and Skeletal Metastases

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Radium-223 chloride (Xofigo®, BAY88-8223) injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Hormone refractory with evidence of rising prostate-specific antigen (PSA): Subject must be maintained on androgen ablation therapy with luteinizing hormone-releasing hormone agonist or have undergone bilateral orchiectomy Serum testosterone level required to be ≤50 ng/dL Subjects who have received prior antiandrogen drug therapy: Flutamide, nilutamide, or cyproterone acetate must have stopped at least 4 weeks prior to study drug administration and progression, as defined by rising PSA as defined below, must have been demonstrated since cessation; bicalutamide must have stopped at least 6 weeks prior to study drug administration and progression, as defined by rising PSA as defined below, must have been demonstrated since cessation PSA progression: Progressive rise in PSA, defined as two consecutive increases in PSA documented over a previous reference value (measure 1). The first increase in PSA (measure 2) should occur at a minimum of 1 week from the reference value (measure 1). This increase in PSA should be confirmed (measure 3) after a minimum of 1 week. If the confirmatory PSA value (measure 3) is less than the previous value, the subject will still be eligible provided the next PSA measure (measure 4) is found to be greater than the second PSA value (measure 2) Skeletal metastases confirmed by bone scintigraphy within the last 6 weeks Performance status: Eastern Co-operative Oncology Group (ECOG) 0-2 Life expectancy: ≥6 months Laboratory requirements: Neutrophil count ≥1.5 x 109/L, platelet count ≥100 x109/L, haemoglobin ≥95 g/L, total bilirubin level within normal institutional limits, aspartate aminotransferase and alanine aminotransferase ≤2.5 times upper institutional limit of the normal range, S Creatinine ≤1.5 times upper institutional limit of the normal range Exclusion Criteria: Has received an investigational drug within 4 weeks prior to the administration of radium-223, or is scheduled to receive one during the treatment and post-treatment period Has received chemo-, immunotherapy, or external radiotherapy within the last 4 weeks prior to administration of study drug, or has not recovered from adverse events due to agents administered more than 4 weeks earlier More than one regimen of previous cytotoxic chemotherapy Has received prior hemibody external radiotherapy Has a need for immediate external radiotherapy Has received systemic radiotherapy with radium-223, strontium-89, samarium-153, rhenium-186 or rhenium-188 for the treatment of bony metastases within the last year prior to administration of study drug Has started treatment with bisphosphonates less than 3 months prior to administration of study drug. Patients are allowed to be on bisphosphonates provided patient is on a stable dose for >/= 12 weeks before administration of study drug Patients who are </= 4 weeks (6 weeks for bicalutamide) post withdrawal of antiandrogen therapy Patients who have started or stopped systemic steroids, within a week prior to study drug administration, or are expected to be subject to changes in the systemic steroid medication Other currently active (relapse within the last 3 years) malignancy (except non-melanoma skin cancer) that are not prostate cancer metastases Visceral (e.g. liver, lung) metastases from prostate cancer as assessed by abdominal/ pelvic CT or chest radiograph within six weeks before administration of study drug Lymph node metastases with short-axis diameter greater than 2 cm Bulky loco-regional disease Any other serious illness or medical condition, for example: any uncontrolled infection, any patient who has clinical heart failure severe enough to cause marked limitation of activity, and who is only comfortable at rest; or any patient who has heart failure more severe than this (NYHA Heart Failure Class III or IV), Crohns disease or ulcerative colitis

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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 chloride<br>IV administrations of 100 kBq/kg b.w (=110 kBq/kg based on the 2015 National Institute of Standards and Technology standardization). Two administrations took place with an interval of 6 weeks | Drug: Radium-223 chloride (Xofigo®, BAY88-8223) injection<br>* Sterile, clear and colourless aqueous solution of radium-223 chloride free of endotoxins, for intravenous administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimation of whole-body retention of radioactivity at each imaging time post-injection |  | 1 week | 
| Estimation of the individual organ uptake/retention of radioactivity at each time-point post injection |  | 1 week | 
| Estimate retention of administered radioactivity in blood |  | Up to 1 week | 
| Estimation of elimination of radioactivity in urine and faeces |  | 2 days | 
| Calculation of estimated absorbed radiation dose to target organs |  | 1 week | 
| Pharmacokinetics |  | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the biodistribution and dosimetry after the first and second injection |  | 7 weeks | 
| Prostate specific antigen (PSA) response | PSA decline, defined as the number of patients with a confirmed ≥50% reduction in PSA level after treatment with respect to the pre-injection PSA level and the time to PSA progression after PSA response | At baseline, before injections, and at 2 month intervals during the 12 month follow up period | 
| Survival |  | 6 and 12 months after the first injection | 
| Adverse events |  | 1 year | 
| Laboratory variables; serum biochemistry and haematology |  | 1 year | 
| Vital signs | Systolic/diastolic blood pressure, respiratory rate, heart rate and body temperature | 12 weeks | 
| ECG (12 leads) | Electrocardiogram (12 leads) | 12 weeks | 
| Physical examination |  | 1 year |