A Randomized Phase IIa Efficacy and Safety Study of Radium-223 Dichloride With Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (CRPC)

Study Overview
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Brief Summary
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The primary objective in this study is to evaluate bone scan response at Week 24 based on the quantified technetium-99 bone scan lesion area (BSLA). The safety of radium-223 dichloride in combination with abiraterone acetate or enzalutamide will be investigated. The study will evaluate radiological progression free survival, overall survival, and skeletal events. This study will also explore the clinical utility of different imaging modalities (whole body quantified technetium-99 bone scan, DW-MRI [diffusion-weighted magnetic resonance imaging] and NaF [sodium fluoride] PET-CT [positron emission tomography-computed tomography] scan) and will have a separate central radiological review for applicable secondary and exploratory imaging endpoints. All subjects will be randomized as assigned randomly by the IXRS (interactive voice / web response system) system in a 1:1:1 ratio into one of the treatment arms: radium-223 dichloride alone, 50 kBq/kg (55 kBq/kg after implementation of NIST [National Institute of Standards and Technology] update) every 4 weeks for up to 6 doses; radium-223 dichloride, 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks up to 6 doses together with abiraterone acetate 1,000 mg daily and prednisone 5 mg bid (twice daily); radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks up to 6 doses together with enzalutamide 160 mg daily. The study will consist of screening, treatment and follow-up periods. Study will continue until disease progression as determined by investigator, or when patient meets criteria for withdrawal from study. Subjects in treatment arms with abiraterone/prednisone or enzalutamide will have the option to continue taking oral study therapy until the end of the study (2 years from the last dose of radium-223 dichloride) if the investigator deems the subject may benefit and there is no clinical or radiological progression. Subjects who discontinue all study treatment prior to 2 years from last radium-223 dichloride treatment will enter active follow-up. During the active follow-up period, the subject will have a safety visit at the clinic every 12 weeks from the EOT (end of treatment) for up to 2 years from the last dose of radium-223 dichloride. Beyond 2 years from last radium-223 dichloride treatment,subjects will enter long-term follow-up and will be followed via phone contact at intervals to assess for safety (hematological toxicity and new primary malignancies) and overall survival. A separate long-term safety follow-up study protocol is planned. Once implemented, the study subjects surviving after the end of the active follow-up will be transitioned to this separate long-term safety follow-up protocol.

Official Title
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A Randomized Open-label Phase IIa Study Evaluating Quantified Bone Scan Response Following Treatment With Radium-223 Dichloride Alone or in Combination With Abiraterone Acetate or Enzalutamide in Subjects With Castration-resistant Prostate Cancer Who Have Bone Metastases

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
* Drug: Abiraterone acetate
* Drug: Prednisone
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Known castration-resistant disease Serum PSA ≥2 ng/mL (μg/L) Multiple skeletal metastases (≥2 hot spots) on bone scan Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2. Life expectancy ≥6 months Adequate hematologic, hepatic, and renal function Exclusion Criteria: History of visceral metastasis, or visceral metastases Malignant lymphadenopathy with lymph nodes exceeding 3 cm in short axis diameter Medical condition that would make prednisone (corticosteroid) use contraindicated Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone bid Treatment with more than one chemotherapy agent for prostate cancer Prior systemic radiotherapy and hemibody external radiotherapy History of pituitary or adrenal dysfunction Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone) Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy History of seizures (taking/not taking anticonvulsants), arteriovenous malformation in the brain, head trauma with loss of consciousness Central nervous system (CNS) metastases

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride (Xofigo, BAY88-8223)<br> | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Radium-223 dichloride (Xofigo, BAY88-8223) 50 kBq/kg (55 kBq/kg after implementation of NIST [National Institute of Standards and Technology] update) every 4 weeks x 6 doses intravenous slow bolus<br>|
| Experimental: Radium-223 with abiraterone&prednisone<br> | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Radium-223 dichloride (Xofigo, BAY88-8223) 50 kBq/kg (55 kBq/kg after implementation of NIST [National Institute of Standards and Technology] update) every 4 weeks x 6 doses intravenous slow bolus<br>Drug: Abiraterone acetate<br>* Abiraterone acetate 1000 mg (4 x 250 mg tablets) taken orally once daily for up to two years following last dose of radium-223 dichloride<br>Drug: Prednisone<br>* Prednisone 5 mg capsule taken orally twice daily for up to two years following last dose of radium-223 dichloride<br>|
| Experimental: Radium-223 with enzalutamide<br> | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Radium-223 dichloride (Xofigo, BAY88-8223) 50 kBq/kg (55 kBq/kg after implementation of NIST [National Institute of Standards and Technology] update) every 4 weeks x 6 doses intravenous slow bolus<br>Drug: Enzalutamide<br>* Enzalutamide 160 mg (four 40 mg capsules) taken orally once daily for up to two years following last dose of radium-223 dichloride<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Bone Scan Response Rate | Radiological bone scan response based on change from baseline of digitized technetium-99 bone scans using computer-aided detection software. Responder (R): 30% or greater resolution of the BSLA compared to baseline. Stable Disease (SD): Not meeting the criteria for R, PD, or UE. Progressive Disease (PD): Two or more new areas of radiotracer uptake attributable to metastatic disease in regions of bone that had not previously shown radiotracer uptake or greater than 30% increase from baseline in BSLA attributable to metastatic disease. Unable to Evaluate (UE): Assigned if bone scan results cannot be interpreted due to inconsistent image acquisition parameters compared to the reference scan, incomplete imaging, or other similar technical deficiencies. | At 24 weeks | 
| Bone Scan Lesion Area | Bone scan lesion area was defined as the sum of the pixel areas (cm2) of the set of the whole body technetium-99 bone scan imaging pixels identified as bone lesion. | At 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological Progression Free Survival |  | From randomization to radiological disease progression or death from any cause (about 30.82 months ) | 
| Time to Radiological Progression |  | From the randomization date to the date of radiological disease progression (about 30.82months) | 
| Time to Radiological Bone Progression |  | From the randomization date to the date of radiological bone progression (about 30.82 months) | 
| Time to First Symptomatic Skeletal Event |  | From the randomization date to the first SSE on or following the randomization date (about 30.82 months) | 
| Symptomatic Skeletal Event-free Survival |  | From the randomization date to the first SSE on or following the randomization date or death, whichever occurred first (about 32.39 months) | 
| Overall Survival |  | From the randomization date to the date of death due to any cause (about 42.94 months) |