Enzalutamide With or Without Vaccine Therapy for Advanced Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: PROSTVAC (rilimogene galvacirepvec/rilimogene glafolivec) -F/TRICOM; PROSTVAC (rilimogene galvacirepvec/rilimogene glafolivec) -V/TRICOM; Enzalutamide
Intervention description: A recombinant fowlpox virus vector vaccine containing the genes for human prostate-specific antigen (PSA) and three co-stimulatory molecules.; A recombinant vaccinia virus vector vaccine containing the genes for human prostate-specific antigen (PSA) and three co-stimulatory molecules.; An androgen receptor inhibitor.
Intervention MeSH terms: Metronidazole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 57.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Immunotherapy; Gene Transfer; Androgen Receptor Antagonist; PSA; Immune Response

Summary:

      Background:

      - Enzalutamide is a hormone therapy that is used to treat advanced prostate cancer. It is
      given after chemotherapy and surgery to help the body destroy the cancer cells. A new
      possible way of treating prostate cancer is using a vaccine that may help stimulate the
      immune system. It will help white blood cells recognize and kill the cancer cells in and
      around the prostate. Researchers want to see whether this vaccine, given with enzalutamide,
      is more effective at treating advanced prostate cancer than enzalutamide alone.

      Objectives:

      - To compare the safety and effectiveness of enzalutamide with and without vaccine therapy
      for advanced prostate cancer.

      Eligibility:

      - Men at least 18 years of age who have advanced castration-resistant prostate cancer.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected. Imaging studies will be used to monitor the cancer before
           treatment.

        -  Participants will be separated into two groups. One group will have enzalutamide and the
           study vaccine. The other group will have enzalutamide alone.

        -  All participants will take enzalutamide once a day. They will take the drug during
           4-week cycles of treatment.

        -  Treatment will be monitored with frequent blood tests and imaging studies. Participants
           will continue to take the study drug for as long as the cancer does not grow, and the
           side effects are not severe.

        -  The vaccine group of participants will also have the new study vaccine. They will have a
           single injection on the first day of the first study cycle. There will be regular
           booster injections afterward. There will be one on day 15 of the first cycle, the first
           day of the second cycle. The vaccine will then be given every 4 weeks for the next four
           cycles, and then every 12 weeks (every 3 cycles) thereafter. Participants will continue
           to have the study vaccine for as long as the cancer does not grow, and the side effects
           are not severe.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed prostate cancer confirmed
             by either the Laboratory of Pathology at the National Institutes of Health (NIH)
             Clinical Center or Walter Reed National Military Medical Center at Bethesda prior to
             starting this study. If no pathologic specimen is available, patients may enroll with
             a pathologist's report showing a histological diagnosis of prostate cancer and a
             clinical course consistent with the disease.

          -  Castrate testosterone level (<50ng/dl or 1.7nmol /L)

          -  Metastatic disease documented by one of the following:

          -  Metastatic bone disease on an imaging study, or

          -  Soft tissue disease documented by computed tomography (CT)/magnetic resonance imaging
             (MRI), or

          -  Progressive disease at study entry defined as one or more of the following criteria
             occurring in the setting of castrate levels of testosterone:

             i. Radiographic progression defined as any new or enlarging bone lesions or growing
             lymph node disease, consistent with prostate cancer OR

        ii. Prostate-specific antigen (PSA) progression defined by sequence of rising values
        separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (Prostate
        Cancer Clinical Trials Working Group (PCWG2) PSA eligibility criteria). If patients had
        been on flutamide, PSA progression is documented 4 weeks or more after withdrawal.

        The requirement for a 4-6 weeks withdrawal period following discontinuation of flutamide,
        nilutamide or bicalutamide only applies to patients who have been on these drugs for at
        least the prior 6 months. For all other patients they must stop bicalutamide, nilutamide or
        flutamide the day prior to enrollment.

          -  Asymptomatic or mildly symptomatic from prostate cancer; no use of regularly scheduled
             opiate analgesics for prostate cancer-related pain

          -  Patients must agree to continue to continuation of androgen deprivation therapy (ADT)
             with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy

          -  Age greater than or equal to 18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
             (Karnofsky greater than or equal to 80%).

          -  Patients must have normal organ and marrow function as defined below:

          -  absolute neutrophil count greater than or equal to 1,500/mcL

          -  platelets greater than or equal to 100,000/mcL

          -  total bilirubin within normal institutional limits; for patients with Gilbert's
             syndrome, total bilirubin less than or equal to 3.0mg/dL

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase
             (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transferase (SGPT) less
             than or equal to 2.5 times institutional upper limit of normal

          -  creatinine within 1.5 X normal institutional limits, OR

          -  creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
             creatinine levels above institutional normal by Cockcroft-Gault Equation

          -  The effects of enzalutamide alone or in combination with PSA-TRICOM on the developing
             human fetus are unknown. For this reason, men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation and for three (3) months after the last dose of
             enzalutamide. Should a woman become pregnant or suspect she is pregnant while her
             partner is participating in this study, she should inform her treating physician
             immediately.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          -  Patients who are immunocompromised as listed as follows:

          -  Human immunodeficiency virus positivity due to the potential for decreased tolerance
             and may be at risk for severe side effects

          -  Chronic administration (defined as daily or every other day for continued use >14
             days) of systemic corticosteroids (including steroid eye drops) or other immune
             suppressive drugs, within 28 days before the first planned dose of PSA-TRICOM. Nasal,
             or inhaled steroid, and topical steroid creams for small body areas are not excluded.

          -  Patients who have undergone allogeneic peripheral stem cell transplantation, or solid
             organ transplantation requiring immunosuppression

          -  History of splenectomy

          -  History of, or active autoimmune disease (such as Autoimmune neutropenia,
             thrombocytopenia, or hemolytic anemia, systemic lupus erythematosis, Sjogrens
             syndrome, scleroderma, myasthenia gravis, Goodpasture's syndrome, Addisons disease,
             Hashimoto's thyroiditis, Crohn's or Grave's disease). Patients with type 1 diabetes
             mellitus or vitiligo are not excluded if the condition is well controlled.

          -  Patients with a history of brain/leptomeningeal metastasis

          -  Patients who have been treated with abiraterone will be excluded

          -  Patients with history of seizure as an adult including febrile seizure or any
             condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous
             malformation, head trauma with loss of consciousness requiring hospitalization). Also,
             current or prior treatment with anti-epileptic medications for the treatment of
             seizures or history of loss of consciousness. Also transient ischemic attack within 12
             months prior to randomization will not be permitted.

          -  Patients with second malignancy within 3 years of enrollment; Patients curatively
             treated non-melanoma skin cancers or carcinoma in situ of the bladder, are not
             excluded.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine)

          -  Known allergy to eggs, egg products, aminoglycoside antibiotics (for example,
             gentamicin or tobramycin),

          -  History of atopic dermatitis or active skin condition (acute, chronic, exfoliative)
             that disrupts the epidermis

          -  Previous adverse reactions to smallpox vaccination

          -  Unable to avoid close contact or household contact with the following high-risk
             individuals for three weeks after the Day 1 vaccination: (a) children less than or
             equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or
             concurrent extensive eczema or other eczematoid skin disorders, or (d)
             immunocompromised individuals, such as those with human immunodeficiency virus (HIV).

          -  Any condition which, in the opinion of the investigator, would prevent full
             participation in this trial (including the long-term follow-up), or would interfere
             with the evaluation of the trial endpoints.

          -  Patients with prior chemotherapy for nonmetastatic prostate cancer within a year are
             excluded.

          -  Receipt of an investigational agent within 28 days (or 56 days for an antibody-based
             therapy) before the first planned dose of study drugs. (Immune checkpoint inhibitors
             that are antibody-based will only require 28 days before enrollment)

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, uncontrolled hypertension (systolic blood pressure (SBP)>170/ diastolic
             blood pressure (DBP)>105) or psychiatric illness/social situations within 12 months
             that would limit compliance with study requirements.

          -  Use of herbal products that may decrease PSA levels (e.g., saw palmetto)

          -  Any gastrointestinal disease that could hinder the absorption of enzalutamide.

          -  Patients who have had chemotherapy for metastatic castration-resistant prostate
             cancer. (Patients who have had docetaxel for metastatic castration sensitive disease
             per Chemo-hormonal Therapy versus Androgen Ablation Randomized Trial for Extensive
             Disease (CHAARTED) Data35 may enroll as long as they did not have progressive disease
             while on docetaxel and are 6 months removed from treatment, with all treatment related
             toxicities resolving to at least grade 1.)

          -  Patients who have received radiation therapy, radionuclide therapy or undergone
             surgery within certain duration (4 weeks) of enrollment