Study of Sipuleucel-T W/ or W/O Radium-223 in Men With Asymptomatic or Minimally Symptomatic Bone-MCRPC

Study Overview
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Brief Summary
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This clinical trial studies the effect of radium-223 when added to sipuleucel-T for treating castrate-resistant prostate cancer that has spread to the bone. Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate an immune response against prostate cancer. It has been suggested that the immune response may be strengthened by radiation therapy. Therefore this study is testing whether radium-223 added to sipuleucel-T increases the immune response and anti-tumor effect against prostate cancer.

Detailed Description
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This is a randomized study designed to assess the antigen-specific immune response of sipuleucel-T with or without radium-223. Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive sipuleucel-T and radium-223 or sipuleucel-T alone. Subjects in both arms (sipuleucel-T and radium) will undergo a standard 1.5 to 2.0 blood volume leukapheresis, followed approximately 3 days later by an IV infusion of sipuleucel-T. This process will occur a total of 3 times at approximately 2-week intervals. Subjects in Arm 1 will receive a total of 6 infusions of radium-223 at IV dose of 50 kBq/kg at 4-week interval. All participants are allowed to receive the best supportive care which includes secondary hormonal manipulation as required. No chemotherapy, external-beam radiation, or other radionuclides are allowed while on active treatment but are permitted after completion of active treatment. Glucocorticoid-containing treatments should be minimized to less than the equivalent dose of prednisone 10mg daily if feasible for the 3 months following sipuleucel-T therapy. All patients continue medical or surgical castration during treatment.

Official Title
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A Phase 2 Study of Sipuleucel-T With or Without Radium-223 in Men With Asymptomatic or Minimally Symptomatic Bone-Metastatic Castrate-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Radium-223
* Biological: Sipuleucel-T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent provided prior to initiation of study procedures Age ≥ 18 years Histologically documented adenocarcinoma prostate cancer confirmed by a pathology report from prostate biopsy or a radical prostatectomy specimen. If prostatic tumor is of mixed histology, > 50% of the tumor must be adenocarcinoma Bone metastases as manifested by one or more lesions on a bone scan performed within 2 months of screening Castrate-resistant prostate cancer, in the setting of castrate levels of testosterone (≤ 50 ng/dL), defined as current or historical evidence of disease progression concomitant with surgical castration or androgen deprivation therapy (ADT), as demonstrated by two consecutive rises in PSA OR new lesions on bone scan: PSA progression will be defined as 2 rising PSA values compared to a reference value, measured at least 7 days apart and the second value is ≥ 2 ng/mL [1]. It must be documented within 2 months of screening. Appearance of one or more new areas of abnormal uptake on bone scan when compared to imaging studies acquired during castration therapy or against the precastration studies if there was no response. Increased uptake of pre-existing lesions on bone scan does not constitute progression. It must be documented within 4 months of screening Serum PSA ≥ 2.0 ng/mL Screening ECOG perf status ≤ 1 Asymptomatic or minimally symptomatic disease (no narcotic analgesic; other analgesics use is allowed) Prior abiraterone and enzalutamide are permitted, but not required Concurrent osteoclast-inhibitory therapies (zoledronic acid, denosumab) are permitted if patients have been on a stable dose for at least 1 month Adequate screening hematologic, renal, and liver function as evidenced by laboratory test results within the following ranges ≤ 28 days prior to registration: Absolute neutrophil count (ANC) ≥ 1.5 x109/L Platelet count ≥ 100 x109/L Hemoglobin ≥ 10.0 g/dL Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Creatinine ≤ 1.5 x ULN Albumin > 25 g/L Exclusion Criteria: The presence of known lung or liver metastases greater than 1.0 cm in the long axis diameter The presence of lymphadenopathy greater than 3 cm in the short-axis diameter The presence of known brain metastases Spinal cord compression, imminent long bone fracture, or any other condition that, in the opinion of the investigator, is likely to require radiation therapy and/or steroids for pain control during the active phase Previous treatment with chemotherapy for mCRPC (adjuvant chemotherapy is permitted), or chemotherapy for any reason within 2 years prior to registration Intention to receive chemotherapy within 6 months after enrollment in protocol therapy History of radiation therapy, either via external beam or brachytherapy within 28 days prior to registration Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 for the treatment of bony metastases within previous 24 weeks Prior history of other cancers (except non-melanoma skin cancers or low-grade low-stage urothelial cancers) Use of prednisone or equivalent systemic corticosteroid within 2 weeks of treatment. Use of inhaled, intranasal, intra-articular, and topical steroids is allowed. Oral or IV steroids to prevent or treat IV contrast reactions are allowed Use of opioid analgesics for cancer-related pain Use of experimental drug within 4 weeks of treatment Uncontrolled medical conditions including diabetes, heart failure, COPD, ulcerative colitis, or Crohn's disease Uncontrolled fecal incontinence Any medical intervention, any other condition, or any other circumstance which, in the opinion of the investigator, could compromise adherence with study requirements or otherwise compromise the study's objectives

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: sipuleucel-T and radium 223 combination<br>Radium-223 will be administered by intravenous injection over 1 minute at 50kbq (1.35 microcurie) per kg body weight per standard of care every 4 weeks at weeks 0, 4, 8, 12, 16, and 20 Sipuleucel-T will be administered intravenously per standard of care every 2 weeks at weeks 6, 8, and 10 | Drug: Radium-223<br>* 6 infusions of radium-223 with 3 infusions of sipuleucel-T starting after second dose of radium-223<br>* Other names: Xofigo, BAY88-8223;Biological: Sipuleucel-T<br>* 3 infusions of sipuleucel-T alone<br>* Other names: Provenge;|
| Active Comparator: sipuleucel-T alone<br>Sipuleucel-T will be administered intravenously per standard of care every 2 weeks at weeks 6, 8, and 10 | Biological: Sipuleucel-T<br>* 3 infusions of sipuleucel-T alone<br>* Other names: Provenge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Responses to Treatment With Sipuleucel-T (With or Without Radium-223) Measured by Peripheral PA2024 T-cell Proliferation | Peripheral PA2024-specific T-cell proliferation responses using a 3H-thymidine incorporation assay at 6 weeks after the first dose of sipuleucel-T, measured by SI (Stimulation Index [3H-thymidine incorporation in the presence of antigen divided by 3H-thymidine incorporation with media alone] ). | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral PA2024 Specific T-cell Proliferation as Measured by Stimulation Index Over Time | Mean peripheral PA2024 specific T-cell proliferation using a 3H-thymidine incorporation assay reported as SI (Stimulation Index [3H-thymidine incorporation in the presence of antigen divided by 3H-thymidine incorporation with media alone] ) at baseline and 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| Time to Radiographic or Clinical Progression | Number of weeks from baseline until radiographic or clinical progression, whichever comes first. Radiographic progression is assessed by RECIST (Response Evaluation Criteria in Solid Tumors) and PCWG2 criteria (Prostate Cancer Working Group 2). Per RECIST, progression is defined as ≥ 20% and ≥ 5 mm from nadir of the sum of the diameters of target lesions. Per PCWG2 criteria, radiographic progression is defined as ≥ 20% sum of the longest diameter of target lesions, or ≥ 2 new lesions on bone scan from baseline. Clinical progression is defined as new spinal cord or nerve root compression, new pathologic fracture or use of opioid analgesics for cancer-related pain. | Up to 2 years | 
| PSA50 Response (at Least a 50% Decline in PSA) | Number of participants with PSA50 response defined as at least a 50% decline in Prostate Specific Antigen (PSA) from baseline value | Up to 2 years | 
| Peripheral PAP Specific T-cell Proliferation as Measured by Stimulation Index Over Time | Mean peripheral PAP specific T-cell proliferation using a 3H-thymidine incorporation assay reported as SI (Stimulation Index [3H-thymidine incorporation in the presence of antigen divided by 3H-thymidine incorporation with media alone] ) at baseline and 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T | Up to 52 weeks | 
| Peripheral PA2024 Specific T-cell Activation | Mean peripheral PA2024 specific T-cell activation to sipuleucel-T using interferon gamma (IFNγ) enzyme-linked immunosorbent spot (ELISPOT), as measured by cells per 300,000 PBMCs at baseline and weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| Peripheral PAP Specific T-cell Activation | Mean peripheral PAP specific T-cell activation to sipuleucel-T using interferon gamma (IFNγ) enzyme-linked immunosorbent spot (ELISPOT) measured as cells per 300,000 PBMCs at baseline and weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| PA2024 Specific Antibody (IgM) Response | Mean titer of PA2024 specific antibody (IgM) response to sipuleucel-T using enzyme-linked immunosorbent assay (ELISA) at baseline and weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| PA2024 Specific Antibody (IgG) Response | Mean titer of PA2024 specific antibody (IgG) response to sipuleucel-T using enzyme-linked immunosorbent assay (ELISA) at baseline and weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| PAP Specific Antibody (IgG) Response Over Time | Mean titer of PAP specific antibody (IgG) response to sipuleucel-T using enzyme-linked immunosorbent assay (ELISA) at baseline and weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| PAP Specific Antibody (IgM) Response | Mean titer of PAP specific antibody (IgM) response to sipuleucel-T using enzyme-linked immunosorbent assay (ELISA) at baseline and weeks 6, 10, 14, 26, 39, and 52 weeks after the first infusion of sipuleucel-T. | Up to 52 weeks | 
| Sipuleucel-T Product Immune Parameters as Assessed by Number of CD54+ Cells | Mean number of CD54 + cells | Up to 4 weeks | 
| Sipuleucel-T Product Immune Parameters as Assessed by CD54+ Upregulation | Mean CD54+ Upregulation of Sipuleucel-T | Up to 4 weeks | 
| Sipuleucel-T Product Immune Parameters as Assessed by Total Nucleated Cell Count | Mean number of Total Nucleated Cells | Up to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostatic neoplasms, castration-resistant, bone metastasis, radium-223, sipuleucel-T