Bavarian Nordic, Inc. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 3PRÉCIS Background xAndrogen deprivation therapy (ADT) and surveillance are standard therapy options for prostate cancer patients with biochemical progression afte r localized therapy (or non- metastatic castration sensitive prostate cancer; nmC SPC also known as D0 Prostate Cancer). These patients cannot be cured of pr ostate cancer and the primary therapeutic goal is to contain the disease with anti-androgen therapy. xADT can be administered intermittently consisting of multiple short courses or continuously with similar long-term clinical outcomes. xPrevious studies with high dose bicalutamide (androgen receptor antagonist, ARA) haveshown significant biochemical control in nmCSPC. xEnzalutamide is a modern ARA with greater andr ogen receptor affinity than bicalutamide and further impairs downstream effects of a ndrogen receptor activation. This agent is FDA approved for the treatment of chemot herapy refractory metastatic castration resistant prostate cancer. xGiven its favorable side effect profile, there is strong interest in using enzalutamide to treat patients with earlier stages of prostate cancer including nmCSPC. xPSA-TRICOM (Prostvac™; developed by the National Cancer Institute [NCI] and licensed to Bavarian Nordic, Mountain View , CA) is a novel candidate prostate cancer immunotherapy for the treatment of prostate cancer. It is a vi ral vector based therapeutic cancer vaccine that is administered via s ubcutaneous 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. xThere 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. xAn ongoing NCI clinical trial that combined PSA-TRICOM with flutamide (an older FDA approved ARA) in nonmetastatic castrat ion resistant pros tate cancer has demonstrated safety and suggested the potential to improve time to progression. xAnalysis 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. xIf 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. xTo 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. xPreliminary data from the first cohort of ra ndomized patients suggests that enzalutamide alone can induce an immunologic response. A second cohort of 15 patients will explore a Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 4lower dose of enzalutamide at 80 mg to de termine if similar immunologic responses can also be seen at a lower dose, where toxicity is less likely. Objectives Primary Endpoint: xDetermine if PSA-TRICOM combined with the novel androgen receptor antagonist enzalutamide will result in a decrease in PSA growth kinestics (tumor re-growth rate)after enzalutamide discontinua tion in patients with non-meta static, castration sensitive prostate cancer (i.e. patient s with normal testosterone). Eligibility xPatients with nonmetastatic cas tration sensitive prostate ca ncer and a PSA over 2.0 ng/ml xPatients with normal testosterone levels. xHistologically confirme d adenocarcinoma. xPatients with a PSA doubling time of 12 months or less. xECOG 0-1. Design xRandomized pilot study xCohort 1: Thirty-four patients to be en rolled and randomized 1:1 to oArm A: Enzalutamide for 3 months. oArm B: Enzalutamide 3 months + PSA-TRICOM on weeks 1, 3,5,9,13,17 and 21. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 5xEnzalutamide will be given at the standard dose of 160 mg daily for 3 months. PSA- TRICOM (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 re treated 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. R A ND O M I Z E Arm A: Enzalutamide (n=17) Arm B: Enzalutamide + PSA-TRICOM (n=17) Cohort 1 Arm A: Enzalutamide (n=17) Arm B: Enzalutamide + PSA-TRICOM (n=17) Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 6TABLE OF CONTENTS SUMMARY OF CHANGES......................................................... Error!