PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer

Study Overview
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Brief Summary
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Background: The immune system is the cells and organs in the body that recognize and fight infection and cancer. The PROSTVAC vaccine might teach the immune system to find and kill certain prostate cancer cells. Nivolumab is a drug that allows the immune system to fight tumors. Itmight help PROSTVAC work better. Objective: To test the safety and effectiveness of the combination of PROSTVAC and nivolumab. To test this for people with castration resistant prostate cancer and then for other people with localized prostate cancer who are candidates for surgical removal of the prostate. Eligibility: Men ages 18 and older with prostate cancer Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Electrocardiogram Bone scan CT scan or MRI Tumor sample. This may be from a previous procedure. All participants will get a combination of the study drugs over 8 weeks. They will have 1 visit for the initial injection then 3 booster injection / nivolumab infusion visits. Blood will be tested at these visits. Over the next 4 weeks, some participants will have: An exam of the large intestine through the rectum. CT and bone scans Standard hormonal treatment Option to continue treatment every 3 weeks if their disease does not get worse. They will be have scans every 12 weeks. Other participants will have surgery to remove the prostate in week 9. Participants will have a safety visit about a month after their last treatment. This will include a physical exam, blood tests, and possibly scans. If their cancer progresses, participants will leave the study and may enroll in a long-term follow-up study. They will be contacted once a year to ask about their cancer and treatment.

Detailed Description
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Background: Immune checkpoint inhibitors interfere with the immune system s autoregulatory mechanisms, allowing for a potentially expanded and prolonged T-cell response with the possibility of greater antitumor effects. Nivolumab is a fully human IgG4 monoclonal antibody that targets the PD-1 protein. Specifically, the antibody binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response. PROSTVAC (developed by the National Cancer Institute [NCI] and licensed to Bavarian Nordic Immunotherapeutics, Mountain View, CA) is a therapeutic cancer vaccine for prostate cancer. Early studies have demonstrated immunologic efficacy and suggested clinical benefit. A phase III trial has completed accrual. A previous study combining the immune checkpoint inhibitor ipilimumab and PROSTVAC suggested greater efficacy than PROSTVAC alone. Additional studies have demonstrated the potential efficacy of immunologic combination therapy with the immune checkpoint inhibitor nivolumab. This study will aim to evaluate the impact of the combination of PROSTVAC and the immune checkpoint inhibitor nivolumab on the tumor microenvironment focusing on immune cell infiltration as the primary endpoint. US-MRI imaging technology will be employed to sample the tumor before treatment and after radical prostatectomy. The findings from this study could serve as the basis for future studies with this combination in this population of participants and more advanced disease. Objectives: Safety (For castration resistant prostate cancer (CRPC) lead-in cohort) Evaluate changes in T-cell infiltration in the tumor after neoadjuvant treatment with PROSTVAC and nivolumab, relative to changes seen in a phase 2 trial with PROSTVAC alone in the neoadjuvant setting- NCT02153918 (For the neoadjuvant cohort). Eligibility: Participants must have histopathological documentation of adenocarcinoma of the prostate prior to starting this study and evaluable biopsy tissue (e.g., unstained slides or blocks) available for analysis. For the castration resistant lead in cohort, if histopathological documentation is unavailable, a rising PSA and a clinical course consistent with prostate cancer would be acceptable. Participants must have a performance status of 0 to 1 according to the ECOG criteria. Hematological eligibility parameters (within 16 days of starting therapy): Granulocyte count 1,500/mm^3 Platelet count 100,000/mm^3 Hgb >= 8 g/dL Biochemical eligibility parameters (within 16 days of starting therapy): Hepatic function: Bilirubin < 1.5 mg/dl (OR in participants with Gilbert s syndrome, total bilirubin <= 3.0 mg/dL), AST and ALT <= 2.5 times upper limit of normal. Creatinine <= 1.5 X ULN Design: The primary focus of this study will be to evaluate PROSTVAC and nivolumab in the neoadjuvant setting. Lead-in cohort evaluating the safety and tolerability of this combination in the castration resistant setting (CRPC cohort) Following this lead-in cohort in the CRPC setting, we will enroll a cohort in the neoadjuvant setting evaluating the combination of PROSTVAC and nivolumab. The lead-in safety cohort will require 10 participants and the neoadjuvant cohort will require 17 evaluable participants. In order to allow for a small number of inevaluable participants, the accrual ceiling will be set to 29 participants.

Official Title
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Phase I/II Study of PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: PROSTVAC-V/F
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: For the neoadjuvant cohort, patients must have histopathological documentation of adenocarcinoma of the prostate prior to starting this study and evaluable biopsy tissue (e.g., unstained slides or blocks) available for analysis. If evaluable tissue is not available, the patient must agree to undergo a pre-vaccination prostate biopsy on study. For the CRPC lead in cohort, if histopathological documentation is unavailable, a rising PSA and a clinical course consistent with prostate cancer would be acceptable. Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of PROSTVAC in combination with nivolumab, ipilimumab or both in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. ECOG performance status of 0 or 1. Participants must not have other active invasive malignancies within the past 2 years (with the exception of non-melanoma skin cancers) (for CRPC cohort only). Participants must be willing to travel to the study site for follow-up visits All participants who have received prior vaccination with vaccinia virus (for smallpox immunization) must not have a history of serious adverse reaction to the vaccine. The effects of PROSTVAC in combination nivolumab, ipilimumab or both on the developing human fetus are unknown. For this reason men must agree to use adequate contraception (abstinence, vasectomy) or female partner must use (intrauterine device (IUD), hormonal [birth control, pills, injections, or implants], tubal ligation] prior to study entry and for up to 7 months after the last dose. Participants must understand and sign informed consent that explains the neoplastic nature of their disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, potential risks and toxicities, and the voluntary nature of participation. Participants must have normal organ and marrow function as defined below: hemoglobin greater than or equal to 8 g/dL granulocytes greater than or equal to 1,500/mcL platelets greater than or equal to 100,000/mcL total bilirubin < 1.5 mg/dL (or less than or equal to 3.0 mg/dL in patients with Gilbert syndrome) AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal creatinine less than or equal to 1.5 X ULN For the lead in cohort: Castrate testosterone level (<50ng/dl or 1.7nmol /L) Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone: Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria). If participants had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal. Participants must agree to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone agonist/antagonist or bilateral orchiectomy For all neoadjuvant cohorts: Participants must be a surgical candidate for radical prostatectomy based on standard workup of PSA, biopsy results, and if necessary supplemental imaging. Participants must have chosen radical prostatectomy as their definitive treatment of choice for management of their prostate cancer. No systemic steroid or steroid eye drop use within 2 weeks prior to initiation of experimental therapy. Limited doses of systemic steroids to prevent IV contrast, allergic reaction or anaphylaxis (in patients who have known contrast allergies) are allowed. EXCLUSION CRITERIA: Prior splenectomy. The recombinant vaccinia vaccine should not be administered if the following apply to either recipients or, for at least 3 weeks after vaccination, their close household contacts (Close household contacts are those who share housing or have close physical contact): persons with active or a history of eczema or other eczematoid skin disorders those with other acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne or other open rashes or wounds) until condition resolves pregnant or nursing women; children under 3 years of age Participants should have no evidence, as listed below, of being immunocompromised: HIV positivity due to the potential for decreased tolerance and risk for severe side effects. Hepatitis B or C positivity. Concurrent use of systemic steroids or steroid eye drops. This is to avoid immunosuppression which may lead to potential complications with vaccinia (priming vaccination). Nasal, topical or inhaled steroid use is permitted. Participants with known allergy to eggs or to compounds with a similar chemical or biologic composition to PROSTVAC, ipilimumab or nivolumab. No prior immune checkpoint inhibitors (e.g., anti-CTLA4, anti-PD-1 or anti-PDL1) are allowed. Other serious intercurrent illness. Participants with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or New York Heart Association class II IV congestive heart failure. Participants with significant autoimmune disease that is active or potentially life threatening if activated. Participants with clinically significant cardiomyopathy requiring treatment. Participants with ongoing toxicities related to prior therapies targeting T cell coregulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody are excluded No transfusion of blood or blood products within 2 weeks and no G-CSF or GM-CSF within 2 weeks prior to initiations of experimental therapy. Contraindication to biopsy or prostatectomy (for sequential neoadjuvant cohorts only): Bleeding disorders Artificial heart valve PT/PTT greater than or equal to 1.5 in participants not taking anticoagulation. Participants on anticoagulation (e.g. enoxaparin, oral anticoagulants) are eligible regardless of PT/PTT. Prior to biopsy, anticoagulation will be held per standard practice. For participants with localized prostate cancer contraindication to MRI: Participants weighing >136 kilograms (weight limit for the scanner tables) Allergy to MR contrast agent Participants with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable electronic devices History of radiation proctitis (for lead-in CRPC cohort only)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in mCRPC Cohort<br>PROSTVAC-V on week 0 followed by booster injection called PROSTVAC-F every 2 weeks. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo sigmoidoscopies on week 9 and restaging scans on week 12. If no PD, option to continue treatment every 2 weeks until intolerance or progression. Option to extend nivolumab interval to 4 weeks after 1 year | Biological: PROSTVAC-V/F<br>* PROSTVAC-V (vaccinia) will be administered subcutaneously in an extremity (e.g., thigh) at a dose of 2x10^8 infectious units. PROSTVAC-F (fowlpox) will be administered subcutaneously in an extremity (e.g., thigh) at a dose of 1x109 infectious units.<br>Drug: Nivolumab<br>* Nivolumab is to be administered as a flat dose over approximately 60-minutes via IV infusion.<br>|
| Experimental: Neoadjuvant Cohort<br>PROSTVAC-V on week 0 followed by booster injection called PROSTVAC-F on 2, 4 and 8 weeks. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo prostatectomy on week 9. | Biological: PROSTVAC-V/F<br>* PROSTVAC-V (vaccinia) will be administered subcutaneously in an extremity (e.g., thigh) at a dose of 2x10^8 infectious units. PROSTVAC-F (fowlpox) will be administered subcutaneously in an extremity (e.g., thigh) at a dose of 1x109 infectious units.<br>Drug: Nivolumab<br>* Nivolumab is to be administered as a flat dose over approximately 60-minutes via IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - lead-in mCRPC cohort | Detection of clinically important inflammation defined as a grade 3 diarrhea or colitis requiring steroids or anti cytokine therapy or not resolving to grade 1 or less within 28 days. | after 10 participants | 
| Evaluate changes in T-cell infiltration in the tumor after neoadjuvant treatment | Evaluate changes in T-cell infiltration in the tumor after neoadjuvant treatment with PROSTVAC and nivolumab, relative to changes seen in a phase 2 trial with PROSTVAC alone in the neoadjuvant setting NCT02153918 (For neoadjuvant cohort). | from baseline to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (for localized prostate cancer cohorts) | Safety | 3-5 years | 
| Evaluate changes in soluble immune mediating factors (such as cytokines, etc.) in sera | Changes in soluble immune mediating factors | 3-5 years | 
| Evaluate changes in PDL-1 expression | Changes in PDL-1 expression | 3-5 years | 
| Evaluate changes in immune cell subsets in the periphery | Changes in immune cell subsets | 3-5 years | 
| Evaluate changes in circulating tumor cells levels (for mCRPC cohort only) | Changes in circulating tumor cells | 3-5 years | 
| Document pathologic responses (including pathologic CR) | Pathologic responses | 3-5 years | 
| Document any PSA changes secondary to vaccination, including rate of biochemical recurrence after prostatectomy | PSA changes | 3-5 years | 
| Document any MRI changes secondary to treatment | MRI changes | 3-5 years | 
| Document any intraprostatic Treg cell infiltration with CD4+FOX-P3 staining | Intraprostatic Treg cell infiltration | 3-5 years | 
| Determine the change in peripheral PSA-specific T cells in participants treated with PROSTVAC and nivolumab | Change in peripheral PSA-specific T cells | 3-5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Neoadjuvant, Prostatectomy, Immunotherapy, Vaccine