Sipuleucel-T With Immediate vs. Delayed Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) Blockade for Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to find out what effects taking ipilimumab, as an immediate or delayed treatment, following completion of sipuleucel-T (SipT) treatment, has on patients and their prostate cancer.

Detailed Description
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This is an open-label randomized multicenter Phase 2 clinical trial combining SipT with ipilimumab in patients with chemotherapy-naïve metastatic castration resistant prostate cancer (CRPC). All patients will be treated with standard SipT (Q2wks x 3). Patients will be randomized to one of two arms: Arm 1 (Immediate Treatment): Ipilimumab Q3wks x 4 started 1 day following the final dose of SipT (Day 0). Arm 2 (Delayed Treatment): Ipilimumab Q3wks x 4 started 3 weeks following the final dose of SipT (Day 0). Following this ipilimumab treatment, patients will then be followed monthly for 3 months and then quarterly until disease progression. The definition of unacceptable toxicity is grade 3 or higher treatment-related toxicities (NCI CTCAE v4) excluding immune-related adverse events (irAEs). The study will assess for the immunogenicity and clinical activity of sequential sipuleucel-T treatment followed by ipilimumab. Patients who experience an initial clinical response to ipilimumab followed by subsequent disease progression will be offered reinduction treatment with ipilimumab.

Official Title
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A Randomized Phase 2 Trial of Immediate vs. Delayed Anti-CTLA4 Blockade Following Sipuleucel-T Treatment for Prostate Cancer Immunotherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: SipT Treatment
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, metastatic prostate adenocarcinoma (positive bone scan and/or measurable disease on CT scan and/or MRI of the abdomen and pelvis). Progressive disease after androgen deprivation, as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) and/or RECIST criteria. Patients must have disease progression by one or both of the following: For patients with measurable disease, progression is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions or the appearance of one or more new lesions, as per RECIST criteria version 1.1. For patients with no measurable disease, a positive bone scan and elevated prostate specific antigen (PSA) will be required. PSA evidence for progressive prostate cancer consists of a PSA level of at least 2 ng/milliliter (mL), which has risen on at least 2 successive occasions, at least 1 week apart. If the confirmatory PSA value is not greater than the screening PSA value, then an additional test for rising PSA will be required to document progression. If no prior orchiectomy has been performed, patients must remain on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist (e.g. degarelix) therapy. Patients who are receiving an antiandrogen as part of primary androgen ablation must demonstrate disease progression following discontinuation of the antiandrogen, defined as two consecutive rising PSA values, obtained at least two weeks apart, or documented osseous or soft tissue progression. At least one of the PSA values must be obtained at least four weeks (flutamide) or six weeks (bicalutamide or nilutamide) after discontinuation. Laboratory requirements: Absolute neutrophil count (ANC) ≥ 1500/μL Bilirubin < 1.5 x upper limit of normal (ULN) Hemoglobin ≥ 8 g/dL PSA ≥ 2 ng/mL Platelets ≥ 100,000/μL aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x ULN Creatinine clearance ≥ 60 mL/min by the Cockcroft Gault equation Testosterone less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1 and life expectancy ≥ 12 weeks. At least 18 years of age or older. Patients receiving any other hormonal therapy, including any dose of megestrol acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA levels (e.g. Saw Palmetto, PC-SPES), or any systemic corticosteroid, must discontinue the agent for at least four weeks prior to study treatment. Progressive disease as defined above must be documented after discontinuation of any hormonal therapy (with the exception of a LHRH agonist). Prior radiation therapy must be completed ≥ 4 weeks prior to enrollment and the patient must have recovered from all toxicity. Prior radiopharmaceuticals (strontium, samarium) must be completed ≥ 8 weeks prior to enrollment. Because of the unknown potential risk to a gamete and/or developing embryo from these investigational therapies, patients must agree to use adequate contraception (barrier method for males) for the duration of study participation, and for three months after discontinuing therapy. Exclusion Criteria: Prior chemotherapy for prostate cancer, with the exception of neoadjuvant chemotherapy, because of the potential effect of chemotherapy on the immune system. Prior sipuleucel-T treatment or investigational immunotherapy. Prostate cancer pain requiring regularly scheduled narcotics. Current treatment with systemic steroid therapy (inhaled/topical steroids are acceptable). Systemic corticosteroids must be discontinued for at least 4 weeks prior to first treatment. History of autoimmune disease including, but not limited to: Systemic lupus erythematosis (SLE), scleroderma, CREST syndrome, rheumatoid arthritis Inflammatory bowel disease, celiac disease, primary biliary cirrhosis, autoimmune hepatitis Dermatomyositis, polymyositis, giant cell arteritis Autoimmune hemolytic anemia (AIHA), cryoglobulinemia, antiphospholipid antibody syndrome (APLS) Diabetes mellitus type I, myasthenia gravis, Grave's disease Wegener's granulomatosis or other vasculitis A history of Hashimoto's thyroiditis, psoriasis, or eczema, any of which has been inactive for at least one year, or isolated Raynaud's phenomenon is acceptable Known central nervous system or visceral metastases. Medical or psychiatric illness that would, in the opinion of the investigator, preclude participation in the study or the ability of patients to provide informed consent for themselves. Cardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association Class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months). Concurrent or prior malignancy except for the following: Adequately treated basal or squamous cell skin cancer Adequately treated stage I or II cancer from which the patient is currently in complete remission Any other cancer from which the patient has been disease-free for 5 years Known HIV or other history of immunodeficiency disorder. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or medical (e.g. infectious) illness. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of adverse events (AE), such as a condition associated with frequent diarrhea. A history of prior treatment with ipilimumab or prior cluster of differentiation 137 (CD137) agonist or CTLA-4 inhibitor or agonist.

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: Immediate IpilimumabTreatment<br>Arm 1 (Immediate Treatment) Ipilimumab Q3wks x 4 started 1 day following the final dose of SipT. | Drug: SipT Treatment<br>* All patients will receive standard of care SipT treatment every two weeks for a total of 3 treatments. The three treatments usually take about 30 days to complete. SipT treatment is given in three 1 hour infusions. Each SipT treatment is generated from a standard blood cell-collection procedure (called leukapheresis) performed 2-3 days prior to the infusion.<br>* Other names: Provenge;Drug: Ipilimumab<br>* Ipilimumab will be given by IV over 90 minutes every 3 weeks. Patients will be monitored during the infusion and up to 1 hour post-infusion.<br>* Other names: BMS-734016/MDX-010, anti-CTLA4;|
| Experimental: Delayed IpilimumabTreatment<br>Arm 2 (Delayed Treatment) Ipilimumab Q3wks x 4 started 3 weeks following the final dose of SipT. | Drug: SipT Treatment<br>* All patients will receive standard of care SipT treatment every two weeks for a total of 3 treatments. The three treatments usually take about 30 days to complete. SipT treatment is given in three 1 hour infusions. Each SipT treatment is generated from a standard blood cell-collection procedure (called leukapheresis) performed 2-3 days prior to the infusion.<br>* Other names: Provenge;Drug: Ipilimumab<br>* Ipilimumab will be given by IV over 90 minutes every 3 weeks. Patients will be monitored during the infusion and up to 1 hour post-infusion.<br>* Other names: BMS-734016/MDX-010, anti-CTLA4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Immune Response to Prostatic Acid Phosphatase (PAP) and/or PA2024 | Immune response will be tested using the single sample binomial exact test when induction therapy is completed. The Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibody responses to PAP and/or PA2024 will be assessed by ELISA assay at baseline and week 20 after start of sipT treatment (day 113 of study treatment). A positive response is defined as a titer > 1:400. The positive immune percentage for both IgG and IgM antibodies to PAP and to PA2024 will be used to summarize the results for each study arm. | Up to 20 weeks | 
| Proportion of Participants With Highest Grade, Treatment-related, Immune Response Adverse Events (IRAEs) | Immune Response Adverse Events (IRAEs) will be reported for each study arm by tabulating the frequency of the maximum grade occurring for each patient for each type of iRAE using NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0. IRAEs will be reported as a proportion of the participants in the treatment arm with the associated highest grade IRAE occurrences during protocol therapy. | Up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving a Prostate-specific Antigen (PSA) Decline of at Least 30% Below Baseline | Descriptive statistics will be calculated to characterize the proportion of patients achieving a PSA decline of at least >30% after 1 cycle of treatment and presented along with the 95% confidence intervals for each study arm. | Up to 3 weeks | 
| Proportion of Patients Achieving a PSA Decline of at Least 50% Below Baseline | Descriptive statistics will be calculated to characterize the proportion of patients achieving a PSA decline of at least >50% and presented along with the 95% confidence intervals for each study arm. | Up to 3 weeks | 
| Proportion of Patients Achieving an Objective Response | Proportion of patients achieving an objective response as defined by Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) as complete response (irCR), partial response (irPR) will be reported along with 95% confidence intervals | Up to 2 years | 
| Proportion of Patients Achieving an Objective Response Stratified by Prior Radical Prostatectomy (RP) | Proportion of patients achieving an objective response as defined by irRECIST as irCR +irPR and stratified by history of prior RP will be reported along with 95% confidence intervals. | Up to 2 years | 
| Proportion of Patients Achieving an Objective Response Stratified by Radiation Therapy (RT) | Proportion of patients achieving an objective response as defined by irRECIST as irCR + irPR stratified by prior RT will be reported along with 95% confidence intervals | Up to 2 years | 
| Radiographic Clinical Response Rate | For each treatment arm, for patients with objective disease, using immune-related response criteria (irRC) criteria, the proportion of patients achieving a complete or partial response will be determined and reported with 95% confidence intervals | Up to 6 months | 
| Median Time to PSA Progression | Time to PSA progression is defined as the start of protocol therapy to progression status at the end of 4 cycles of treatment as determined by the irRECIST. | Up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ipilimumab, castration resistant, prostate, cancer, provenge, SipT