Patient case: 74-year-old female with melanoma; genetic feature: no tumor infiltrating lymphocytes

Clinical trial: PROSTVAC in Combination With Nivolumab and/or Ipilimumab in Men With Prostate Cancer

Summary: 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 and ipilimumab are drugs that allow the immune system to fight tumors. They might help PROSTVAC work better.
  Objective:
  To test the safety and effectiveness of the combination of PROSTVAC, nivolumab, and ipilimumab. To test this for people with castrate resistant prostate cancer and then for other people with prostate cancer.
  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 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: 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.
  -  Ipilimumab, a fully human anti-CTLA-4 monoclonal antibody, is a first-in-class immune checkpoint inhibitor. CTLA-4 is expressed on cytotoxic T lymphocytes (CTLs) after activation by APCs.
  -  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 ipilimumab and a second immune checkpoint inhibitor nivolumab.
  -  This study will aim to evaluate the impact of immunologic combinations 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 these combinations in this population of patients 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 ipilimumab, and PROSTVAC and nivolumab, relative to changes seen with PROSTVAC, ipilimumab and nivolumab (For all other cohorts).
  Eligibility:
  -  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.
  -  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.
  -  Patients 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 greater than or equal to 8 g/dL
  -  Biochemical eligibility parameters (within 16 days of starting therapy):
  -  Hepatic function: Bilirubin < 1.5 mg/dl (OR in patients with Gilbert s syndrome, total bilirubin less than or equal to 3.0 mg/dL), AST and ALT less than or equal to 2.5 times upper limit of normal.
  -  Creatinine less than or equal to 1.5 X ULN
  Design:
  -  The primary focus of this study will be to evaluate PROSTVAC, ipilimumab and nivolumab in the neoadjuvant setting.
  -  Lead-in cohort evaluating the safety and tolerability of this combination in the castration resistant setting (CRPC cohort)
  -  This cohort will undergo sigmoidoscopies at 9 weeks to evaluate for any rectal inflammation or colitis which may pose a problem for men in the neoadjuvant cohorts undergoing radical prostatectomy (done at 9 weeks on study).
  -  Following this lead-in cohort in the CRPC setting, we will enroll three sequential cohorts in the neoadjuvant setting.
  -  The first cohort will evaluate the combination of PROSTVAC and nivolumab. The second cohort will evaluate the combination of PROSTVAC and ipilimumab. The final cohort will evaluate the combination of all three.
  -  The lead-in safety cohort will require 10 patients and Cohorts A through C will require 48 evaluable patients. In order to allow for a small number of inevaluable patients, the accrual ceiling will be set to 65 patients.

Eligibility: -  INCLUSION CRITERIA:
  For all cohorts except the CRPC lead in 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 patients <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.
  -  Patients must not have other active invasive malignancies within the past 2 years (with the exception of non-melanoma skin cancers) (for CRPC cohort only).
  -  Patients must be willing to travel to the study site for follow-up visits
  -  All patients who have received prior vaccination with vaccinia virus (for smallpox immunization) must not have a history of 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 5 months after the last dose.
  -  Patients 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.
  -  Patients 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 patients 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.
  -  Patients must agree to continue to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone agonist/antagonist or bilateral orchiectomy
  -  For all other cohorts:
  -  Patients must be a surgical candidate for radical prostatectomy based on standard workup of PSA, biopsy results, and if necessary supplemental imaging.
  -  Patients 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
  -  Patients 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.
  -  Patients 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.
  -  Patients 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.
  -  Patients with significant autoimmune disease that is active or potentially life threatening if activated.
  -  Patients with clinically significant cardiomyopathy requiring treatment.
  -  Patients 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:
  -  Bleeding disorders
  -  PT/PTT greater than or equal to 1.5 times the upper limit of normal
  -  Artificial heart valve
  -  For patients with localized prostate cancer contraindication to MRI:
  -  Patients weighing >136 kilograms (weight limit for the scanner tables)
  -  Allergy to MR contrast agent
  -  Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable electronic devices

Relevance to patient case: not relevant