PRÉCIS......................................................................................................................... ...................3 TABLE OF CONTENTS.................................................................................................................6 1 INTRODUCTION .............................................................................................................11 1.1 Study Objectives ....................................................................................................11 1.1.1 Primary.......................................................................................................11 1.1.2 Secondary...................................................................................................11 1.2 Background and Rationale.....................................................................................11 1.2.1 Enzalutamide..............................................................................................111.2.2 Therapeutic Cancer Vaccin es in Prostate Cancer ......................................13 1.2.3 PSA-TRICOM ...........................................................................................141.2.4 Rationale for Combining En zalutamide with PSA-TRICOM ...................15 1.2.5 Combining Androgen Receptor Antagonists with PSA-TRICOM, clinical evidence.........................................................................................16 ................................................16 1.2.6 Enzalutamide’s Immune Eff ects in Preclinical Models.............................16 1.2.7 Rationale for conducting the study in nmCSPC patients...........................18 1.2.8 The Importance of Evaluating the Immunologic Response.......................181.2.9 Change in regrowth rate as endpoint .........................................................19 1.2.10 Tumor Growth Kinetics .............................................................................21 1.2.11 Rationale for Re-Treatment of Patients with a Se cond Course of Enzalutamide..............................................................................................22 1.2.12 Rationale for Evaluating Change s in Testoster one and Related Hormone Levels.........................................................................................22 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT....................................................23 2.1 Eligibility Criteria ..................................................................................................23 2.1.1 Inclusion Criteria .......................................................................................232.1.2 Exclusion Criteria ......................................................................................242.1.3 Recruitment Strategies...............................................................................26 2.2 Screening Evaluation .............................................................................................262.3 Registration Procedures .........................................................................................262.4 Treatment Assignment and Randomiz ation/Stratifica tion Procedures..................26 2.5 Baseline Evaluation ...............................................................................................27 Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 73 STUDY IMPLEMENTATION .........................................................................................27 3.1 Study Design..........................................................................................................27 3.1.1 Protocol Stopping Rules ............................................................................28 3.2 Drug Administration ..............................................................................................29 3.3 Treatment Modifications........................................................................................29 3.3.1 Vaccine ......................................................................................................29 3.3.2 Enzalutamide..............................................................................................30 3.4 Protocol Evaluation (see Appendix C ) .................................................................30 3.4.1 All patients who are deemed elig ible and who sign an informed consent will be enrolle d in this trial...........................................................30 3.4.2 A complete history and physical examination, including ECOG performance status, will be done within 16 days before enrollment. ........30 3.4.3 Laboratory Studies.....................................................................................30 3.4.4 Radiographic assessment ...........................................................................31 3.4.5 Assessment for PSA-TRICOM administration (Arm B)...........................31 3.5 Concurrent Therapies.............................................................................................31 3.6 Criteria for Removal from Protocol Therapy and Off Study Criteria....................31 3.6.1 Criteria for removal from protocol therapy ...............................................31 3.6.2 Off-Study Criteria ......................................................................................32 3.6.3 Off Protocol Therapy an d Off-Study Procedure........................................32 3.7 Post-Study Evaluation (Follow-Up) ......................................................................32 4 BIOSPECIMEN COLLECTION.......................................................................................32 4.1 Correlative Studies for Re search ...........................................................................32 4.1.1 Immunologic Parameters ...........................................................................32 4.1.2 Collection of Research (I mmunologic) Blood Samples ............................33 4.1.3 Immunologic Assays..................................................................................34 4.1.4 Additional Assays ......................................................................................35 4.1.5 Plasma VEGF levels ..................................................................................36 4.1.6 Serum Analysis ..........................................................................................36 4.2 Storage and Tracking of Collected Blood Samples ...............................................37 4.2.1 Protocol Completion/Sa mple Destruction .................................................38 5 SUPPORTIVE CARE........................................................................................................38 5.1 Excluded medications ............................................................................................39 5.2 Treatment of vaccinia vaccination complication ...................................................39 5.2.1 Vaccinia Immune Globulin:.......................................................................39 5.2.2 Cidofovir (Vistide®, Gilead Sciences):.....................................................40 6 DATA COLLECTION AND EVALUATION..................................................................40 6.1 Data Collection ......................................................................................................40 6.1.1 Eligible patients must be confirmed and checklist completed. Consent form must be signed prior to registration with Central Registration Information Services.