Androgen Deprivation Therapy +/- Radium-223 Dichloride in Metastatic Prostate Cancer With Bone Metastases

Study Overview
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Brief Summary
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Newly diagnosed metastatic prostate cancer subjects with bone metastases will be accrued to this stratified randomized 2-arm Phase II trial. Subjects will be randomized 1:2 to ADT or ADT with Radium-223 dichloride respectively.

Detailed Description
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OUTLINE: This is a multi-center, randomized trial. STRATIFICATION FACTORS: Subjects will be stratified based on serum total alkaline phosphatase at baseline and extent of disease (described below). Randomization will occur within stratification group. Extent of Disease: <6 skeletal metastases with no visceral metastases versus ≥6 skeletal metastases or visceral metastases. Serum total alkaline phosphatase at baseline: normal vs abnormal. Abnormal alkaline phosphatase is defined as > 130 IU/L. Early Induction or Late Induction status will not be a stratification criterion. TREATMENT SCHEDULE: CONTROL ARM A All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH antagonist (degarelix) or bilateral orchiectomy, with dosage determined by the treating physician. Route of administration and cycle days will be administered as per package insert. Androgen deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously. All subjects will receive bicalutamide, 50 mg Oral (PO) Daily TREATMENT SCHEDULE: EXPERIMENTAL ARM B All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH antagonist (degarelix) or bilateral orchiectomy, with dosage determined by the treating physician. Route of administration and cycle days will be administered as per package insert. Androgen deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously. All subjects will receive bicalutamide, 50 mg oral (PO) daily All subjects will receive Radium-223 dichloride, 50 kBq (1.35 microcurie) per kg body weight, intravenous (IV bolus) every 28 days for 6 injections The following laboratory values must be obtained within 28 days prior to registration for protocol therapy: Hematopoietic: Hemoglobin (Hgb) ≥ 8.0 g/dL (80 g/L) without packed RBC transfusion Platelets ≥ 100 K/mm3 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 Hepatic: Total Bilirubin ≤ 2 x institutional upper limit of normal (ULN) except subjects with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x institutional ULN (≤ 5 x institutional ULN in the presence of liver metastases). Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x institutional ULN (≤ 5 × institutional ULN in the presence of liver metastases). Renal: Estimated Creatinine Clearance by Cockcroft-Gault formula ≥ 30 mL/min

Official Title
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Androgen Deprivation Therapy With or Without Radium-223 Dichloride in Patients With Newly Diagnosed Metastatic Prostate Cancer With Bone Metastases: Hoosier Cancer Research Network GU13-170

Conditions
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Prostate Cancer, Bone Metastases, Prostate Neoplasms

Intervention / Treatment
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* Drug: LHRH agonist/antagonist
* Drug: Bicalutamide
* Radiation: Radium-223 dichloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects or their legally authorized representative must be informed of the investigational nature of the study and provide written informed consent and HIPAA authorization for release of personal health information before performance of any study related procedure not part of routine medical care. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Men ≥ 18 years of age at the time of informed consent. Histological or cytological evidence of prostate adenocarcinoma. All subjects must have radiologic or pathologic evidence of ≥ 2 skeletal lesions with or without pain at baseline on bone scan or axial imaging or 1 skeletal lesion and bone pain within 28 days prior to the registration. All subjects must have a radiographic assessment (chest or abdominal/pelvic CT or MRI) within 28 days prior to registration but do not need to have measurable disease. ECOG (Eastern Cooperative Oncology Group) Performance Status of 0-2 within 28 days prior to registration. ECOG Performance Status of 3 will only be allowed if judged by the treating investigator as attributable exclusively to bone pain. Subjects must fall into one of the two populations below: EARLY INDUCTION GROUP: Subjects who have started androgen deprivation therapy (luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with or without an anti-androgen agent) a maximum of 28 days before registration and who otherwise meet all the eligibility criteria. LATE INDUCTION GROUP: Subjects who have NOT started any androgen deprivation therapy (luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with or without an antiandrogen agent). Anti-androgen receptor antagonist therapy must be bicalutamide. Subjects already started on other anti-androgens must be willing to switch over to bicalutamide. Any prior androgen-deprivation therapy or finasteride as neoadjuvant or adjuvant therapy or for biochemical recurrence must have been discontinued at least 6 months prior to registration. Prior surgical treatment for prostate cancer is allowed but must have been completed at least 14 days prior to registration and any toxicity from such therapy must have recovered to ≤ grade 1 per CTCAE version 4 criteria by the time of registration. All subjects, including those who are surgically sterilized, must be willing to use an effective method of contraception (barrier method of birth control or abstinence) from the time informed consent is signed until 6 months after completion of protocol therapy. Subjects must consent to bank whole blood, serum, plasma for future unspecified studies. Exclusion Criteria: Prior cytotoxic chemotherapy for metastatic prostate cancer. Prior cytotoxic chemotherapy with curative intent in the neoadjuvant or adjuvant setting is allowed but must have been completed at least 6 months prior to registration. No cytotoxic chemotherapy is allowed during protocol specified therapy. Prior concomitant therapy with ketoconazole, aminoglutethimide or abiraterone acetate or enzalutamide (MDV3100) or intent to treat with the above. Concurrent megestrol for hot flashes is allowed. Prior or ongoing bisphosphonate (e.g,. zoledronic acid) or RANKL inhibitor (e.g. denosumab) use is NOT allowed except when used solely for osteoporosis and strictly per guidelines for that indication. Bisphosphonate or RANKL inhibitor cannot be initiated for any indication during protocol specified therapy without consent of the sponsor-investigator of the study. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188. Diagnosis of aplastic anemia, pure red cell aplasia, myelodysplasia or any of the other bone marrow failure states. Any neuroendocrine differentiation including small cell carcinoma on histology or cytology. No prior malignancy except for non-melanomatous skin cancer or non-muscle invasive bladder cancer or adequately treated Stage I or II cancer (adequacy at discretion of treating investigator) from which the subject is currently in complete remission, or any other cancer from which the subject has been disease-free for at least 3 years. History of or active CNS metastasis (brain, leptomeningeal or cord compression). Brain imaging studies are not required for eligibility if the subject has no neurologic signs or symptoms suggestive of brain metastasis. Subjects with neurological symptoms are recommended to undergo a head CT scan (with or without intravenous contrast) or brain MRI (with or without intravenous contrast) to exclude brain metastasis. If brain imaging studies are performed, they must be negative for CNS disease. Skull bone involvement without neurological impact by prostate cancer is allowed. Treatment with any other investigational agent within 28 days prior to registration. Subjects must not be treated with any other investigational agent while on protocol specified therapy. Prior hemibody external radiation. Any external radiation therapy must have been completed at least 14 days prior to registration. Any toxicity from such therapy must have recovered to ≤ grade 1 per CTCAE version 4 criteria by the time of registration. Clinically significant infections as judged by the treating investigator. Subjects must not have been diagnosed with human immunodeficiency virus (HIV) infection, active chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation in this study. Subjects should be tested for hepatitis B or C or HIV infection during screening only if they are considered by the investigator to be at high risk for these infections. Known hypersensitivity to bicalutamide. Known gastrointestinal (GI) disease or procedure that could interfere with the GI absorption or tolerance of bicalutamide, including difficulty swallowing oral medications. Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., subjects with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), symptomatic pulmonary embolism within 3 months, unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia as determined by the treating physician.

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 |
| --- | --- |
| Active Comparator: Control Arm A<br>All subjects will receive LHRH agonist/antagonist per dosage and route of administration specified by the treating physician. Bicalutamide, 50mg, PO will be administered daily. Cycles will be 28 days. | Drug: LHRH agonist/antagonist<br>* Treating physician will determine LHRH agonist/antagonist, dosage and route of administration, per package insert, during each 28-day cycle.<br>* Other names: Per treating physician;Drug: Bicalutamide<br>* Bicalutamide, 50 mg Oral (PO) will be administered daily in each 28-day cycle.<br>* Other names: Casodex;|
| Experimental: Experimental Arm B<br>All subjects will receive LHRH agonist/antagonist per dosage and route of administration specified by the treating physician. Bicalutamide, 50mg, PO will be administered daily. Cycles will be 28 days. Radium-223 dichloride, 50 kBq/kg body weight, will be administered as a bolus intravenous (IV) injection at intervals of every 28 days for up to 6 cycles. | Drug: LHRH agonist/antagonist<br>* Treating physician will determine LHRH agonist/antagonist, dosage and route of administration, per package insert, during each 28-day cycle.<br>* Other names: Per treating physician;Drug: Bicalutamide<br>* Bicalutamide, 50 mg Oral (PO) will be administered daily in each 28-day cycle.<br>* Other names: Casodex;Radiation: Radium-223 dichloride<br>* Radium-223 dichloride, 50 kBq (1.35 microcurie) per kg body weight intravenous (IV bolus) every 28 days for 6 injections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological Progression-Free Survival (rPFS) | rPFS assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) to compare outcomes of subjects on experimental arm vs control arm | From date of randomization to disease progression or death from any cause, up to a maximum of 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug, Graded According to NCI Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) | The intensity of AEs for subjects on both arms graded according to CTCAE v4.0 on a five-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening and Death) | From date of first dose until 30 days after the last treatment, assessed for a maximum of 24 months | 
| Time to First Skeletal-Related Event (SRE) | SRE of subjects on both arms assessed by bone scan or axial imaging | From date of first dose until 30 days after the last treatment, assessed for a maximum of 24 months | 
| Secondary Neoplasms | Secondary neoplasms of subjects on both arms assessed by bone scan or axial imaging | From date of first dose until 30 days after the last treatment, assessed for a maximum of 24 months | 
| PSA Complete Response Rates | Subjects on both arms with PSA ≤ 0.2 ng/mL after 7 months of androgen deprivation therapy | From date of first dose of androgen deprivation therapy (ADT) until completion of 7 cycles (28 weeks) | 
| PSA Partial Response Rates | Subjects on both arms with PSA between 0.2 and ≤ 4 ng/mL after 7 months of androgen deprivation therapy. | From date of first dose of ADT until completion of 7 cycles (28 weeks) | 
| Median Time to Castration Resistance | Castration resistance for subjects on both arms determined by first PSA level increase and/or radiographic progression by first imaging assessment showing progression | From date of ADT (first LHRH agonist/antagonist/surgical castration) to date of PSA and/or radiographic progression, assessed for a maximum of 24 months | 
| 2-Year PSA Progression Free Survival (PFS) | PSA PFS for subjects on both arms defined as first PSA level increase | From date of randomization to first occurrence of PSA progression, symptomatic deterioration, or death due to any cause, assessed up to 24 months | 
| 2-Year Overall Survival (OS) | OS for subjects on both arms | From date of randomization to death from any cause, assessed up to 24 months | 
| 12-Week Alkaline Phosphatase (ALP) Normalization | ALP normalization for subjects with abnormal ALP at randomization | From date of randomization until completion of 12 weeks of therapy | 
| Time to ALP Progression | ALP progression of 25% or greater from baseline/nadir for subjects on both arms | From date of randomization until date of ALP progression, assessed up to 24 months | 
| Change in Pain Over Time | Subjects on both arms self-reported evaluation of worst pain item, as well as the subscale scores for pain severity and pain interference as determined by subject responses on the BPI-SF questionnaire. | From baseline until 30 days after the last treatment, assessed for a maximum of 24 months | 
| Analgesic Use by WHO Ladder Score | Analgesic use scores for subjects on both arms will be assigned by the treating physician based on the subject's daily analgesic use on average. A single numeric score (0, 1, 2 or 3) will be assigned based on the 3-step WHO pain ladder. | From baseline until 30 days after the last treatment, assessed for a maximum of 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radium-223 Dichloride, Androgen Deprivation Therapy, Androgen Receptor Antagonist, Placebo