Enzalutamide in Combination With PSA-TRICOM in Patients With Non-Metastatic Castration Sensitive Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Enzalutamide is a well tolerated hormone therapy that is used to treat advanced prostate
      cancer. It is given to help kill cancer cells and limit cancer cell growth. A new possible
      way of treating prostate cancer is using a therapeutic cancer vaccine (immune stimulating
      therapy) that may help activate the immune system against the cancer. The immune stimulating
      vaccine will help white blood cells recognize and kill the cancer cells throughout the body.
      This vaccine therapy has been tested in hundreds of patients and is very well tolerated.
      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.

      Key Eligibility:

        -  Men at least 18 years of age who have advanced castration sensitive prostate cancer.

        -  Patients must have testosterone within the normal range

        -  No evidence of metastatic prostate cancer on computed tomography (CT) or Bone scan

        -  No history of autoimmune diseases

        -  No previous immunotherapy within 3 years

      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 for 3
           months. This form of intermittent therapy is common in this population of patients.

        -  The vaccine group of participants will receive 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 injection during the third week of
           treatment, and one in the fifth week. The vaccine will then be given every 4 weeks until
           21 weeks have passed.

        -  Treatment will be monitored with frequent blood tests and imaging studies.
    

Detailed description: 
      Background:

        -  Androgen deprivation therapy (ADT) and surveillance are standard therapy options for
           prostate cancer patients with biochemical progression after localized therapy (or
           nonmetastatic castration sensitive prostate cancer; nmCSPC also known as D0 Prostate
           Cancer). These patients cannot be cured of prostate cancer and the primary therapeutic
           goal is to contain the disease with anti-androgen therapy.

        -  ADT can be administered intermittently consisting of multiple short courses or
           continuously with similar long-term clinical outcomes.

        -  Previous studies with high dose bicalutamide (androgen receptor antagonist, ARA) have
           shown significant biochemical control in nmCSPC.

        -  Enzalutamide is a modern ARA with greater androgen receptor affinity than bicalutamide
           and further impairs downstream effects of androgen receptor activation. This agent is
           FDA approved for the treatment of chemotherapy refractory metastatic castration
           resistant prostate cancer.

        -  Given its favorable side effect profile, there is strong interest in using enzalutamide
           to treat patients with earlier stages of prostate cancer including nmCSPC.

        -  PSA-TRICOM (Prostvac; developed by the National Cancer Institute [NCI] and licensed to
           Bavarian Nordic, Mountain View, California (CA)) is a novel candidate prostate cancer
           immunotherapy for the treatment of prostate cancer. It is a viral vector based
           therapeutic cancer vaccine that is administered via subcutaneous injections. In a
           randomized controlled Phase 2 trial, PSA-TRICOM therapy was associated with a
           prolongation of survival in men with metastatic castrate-resistant prostate cancer. A
           phase III trial is currently enrolling patients in this same population.

        -  There is also rationale to use therapeutic cancer vaccines such as PSA-TRICOM in earlier
           stage prostate cancer patients to maximize the potential therapeutic effect of immune
           stimulating therapy.

        -  An ongoing NCI clinical trial that combined PSA-TRICOM with flutamide (an older Food and
           Drug Administration (FDA) approved ARA) in nonmetastatic castration resistant prostate
           cancer has demonstrated safety and suggested the potential to improve time to
           progression.

        -  Analysis of previous trials using therapeutic cancer vaccines alone and in combination
           suggests that such therapies may alter tumor growth rate. If this hypothesis is correct,
           a therapeutic cancer vaccine may alter tumor regrowth rate/recovery after a
           cytoreductive therapy such as enzalutamide is discontinued.

        -  If PSA-TRICOM with enzalutamide can result in a reduced tumor regrowth rate as measured
           by PSA after a short course of enzalutamide therapy, it would provide an important proof
           of concept and potentially define it more clear role for therapeutic cancer vaccines in
           prostate cancer and potentially other cancers.

        -  To prospectively evaluate this hypothesis, all patients will be treated with
           enzalutamide in a manner similar to how short course ADT is used in common clinical
           practice. Half the patients will also be given PSA-TRICOM and PSA recovery after
           enzalutamide therapy will be compared between patients who received vaccine and those
           who did not.

        -  Preliminary data from the first cohort of randomized patients suggests that enzalutamide
           alone can induce an immunologic response. A second cohort of 15 patients will explore a
           lower dose of enzalutamide at 80 mg to determine if similar immunologic responses can
           also be seen at a lower dose, where toxicity is less likely.

      Objectives:

      Primary Endpoint:

      -Determine if PSA-TRICOM combined with the novel androgen receptor antagonist enzalutamide
      will result in a decrease in PSA growth kinetics (tumor re-growth rate) after enzalutamide
      discontinuation in patients with non-metastatic, castration sensitive prostate cancer (i.e.
      patients with normal testosterone).

      Eligibility:

        -  Patients with nonmetastatic castration sensitive prostate cancer and a PSA over 2.0
           ng/ml

        -  Patients with normal testosterone levels.

        -  Histologically confirmed adenocarcinoma.

        -  Patients with a PSA doubling time of 12 months or less.

        -  Eastern Cooperative Oncology Group (ECOG) 0-1.

      Design:

        -  Randomized pilot study

        -  Cohort 1:

        -  Thirty-four patients to be enrolled and randomized 1:1 to

             -  Arm A: Enzalutamide for 3 months.

             -  Arm B: Enzalutamide 3 months + PSA-TRICOM on weeks 1, 3,5,9,13,17 and 21.

      Cohort 1:

        -  Arm A: Enzalutamide (n=17)

        -  Arm B: Enzalutamide + PSA-TRICOM (n=17)

             -  Enzalutamide will be given at the standard dose of 160 mg daily for 3 months.
                PSATRICOM (Prostvac-V/F) will consist of a single subcutaneous (sc) immunization of
                Prostvac-V in Week 1, followed by 6 Prostvac-F immunizations administered in Weeks
                3, 5, 9, 13, 17, and 21. Patients will be retreated with a 3-month course of
                enzalutamide after PSA has returned to baseline values at study entry or higher.
                Patients will have had to be on study for at least 7 months or longer in order to
                be retreated with an additional course of enzalutamide therapy. Patients will be
                followed for PSA recovery after enzalutamide has been discontinued. Patients who do
                not develop a 25% decline in PSA after 3 months will not be evaluated for tumor
                re-growth and additional patients will be enrolled to evaluate for that endpoint.
                Patients will be stratified based on a doubling time of greater than or less than 6
                months.
    

Intervention name(s): PROSTVAC-F (Fowlpox)/TRICOM; PROSTVAC-V (Vaccinia)/TRICOM; Enzalutamide (Xtandi)
Intervention type(s): Biological; Biological; Drug
Intervention description(s): 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.
Other intervention name(s): PROSTVAC-F/TRICOM; PROSTVAC-V/TRICOM; Xtandi
Intervention MeSH terms: Metronidazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Gene Transfer; Androgen Receptor Antagonist; PSA; Immune Response; Immunotherapy