Bavarian Nordic, Inc. Commercial Agents: Cidofovir 2 PRÉCIS Background: Enzalutamide is a well-tolerated, modern androgen receptor antagonist (ARA) with more enhanced anti-tumor activity compared to previous ARAs. Phase III trial has demonstrated a 4.8 month improvement in survival and a 37% risk reduction in death in metastatic castration resistant prostate cancer (mCRPC) patients who have had previous docetaxel. PROSTVAC™ is a therapeutic cancer vaccine which is designed to induce an anti-tumor immune response. In a randomized controlled Phase 2 trial, PROSTVAC therapy was associated with a prolongation of survival by 8.5 months in men with metastatic castrate- resistant prostate cancer. An international Phase 3 trial is on-going. Preclinical data has demonstrated that hormonal therapies such as ARAs can enhance the immune response through multiple mechanisms. Specifically, our group has shown that enzalutamide can increase thymic production of naïve T-cells, which could be activated by a cancer vaccine. Together, these data provide an important rationale to combine enzalutamide with PSA-TRICOM in mCRPC. Data from the clinical trials with these therapies suggest that they are very well tolerated and without overlapping toxicity. Objective: Determine if PSA-TRICOM combined with enzalutamide will increase time to progression (as defined by Prostate Cancer Clinical Trials Working Group 2 criteria, incorporated in section 5.2) in chemotherapy-naïve metastatic castration resistant prostate cancer patients compared to enzalutamide alone. Eligibility: mCRPC patients with rising PSA or progressive disease despite castration levels of testosterone. Chemotherapy-naïve with minimal or no symptoms related to prostate cancer. Patients with history of autoimmune disease, brain/leptomeningeal metastasis, a second malignancy within 3 years of enrollment, or a severe co-morbid condition will be excluded. Patients who have received abiraterone will be excluded Patients will be stratified based on previous immunotherapy used as cancer treatment. 3 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 Design: The study will randomize chemotherapy-naïve, mCRPC patients to either enzalutamide alone or enzalutamide with PSA-TRICOM. Enzalutamide will be given at the standard dose of 160 mg daily. PSA-TRICOM will be administered identical to the Phase III dosing with vaccine given week 1 (vaccinia-PSA-TRICOM, 2x108 infectious units subcutaneously) and then week 3, 5 and then monthly fowlpox-vaccine (1x109 infectious units subcutaneously). After completing 6 months of vaccine, fowlpox-vaccine (1x109 infectious units subcutaneously will be administered every 3 months. Patients will be treated until radiographic progression on scans using Prostate Cancer Working Group Criteria. R A N D O M I Z EArm A: Enzaluatmide (n=36) Arm B: Enzaluatmide + PSA-TRICOM (n=36) Patient Population: chemotherapy-naïve, mCRPC 4 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 TABLE OF CONTENTS PRÉCIS............................................................................................................................................2 TABLE OF CONTENTS ................................................................................................................4 STATEMENT OF COMPLIANCE ...........................................................................................10 1. INTRODUCTION .................................................................................................................10 1.1 Study Objectives .............................................................................................................10 1.1.1 Primary Objective....................................................................................................10 1.1.2 Secondary Objectives ..............................................................................................10 1.1.3 Exploratory Objectives ............................................................................................10 1.2 Background and Rationale ..............................................................................................11 1.2.1 Enzalutamide ...........................................................................................................11 1.2.2 Therapeutic Cancer Vaccines in Prostate Cancer....................................................12 1.2.3 PSA-TRICOM .........................................................................................................13 1.2.4 Rationale for Combining Enzalutamide with PSA-TRICOM .................................14 1.2.5 Combining Androgen Receptor Antagonists with PSA-TRICOM .........................15 1.2.6 The Importance of Evaluating the Immunologic Response ....................................17 1.2.7 Rationale for Time to Progression as a Primary Endpoint ......................................17 1.3 Summary of Rationale ....................................................................................................18 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................19 2.1 Eligibility Criteria ...........................................................................................................19 2.1.1 Inclusion Criteria .....................................................................................................19 2.1.2 Exclusion Criteria ....................................................................................................20 2.1.3 Recruitment Strategies.............................................................................................22 2.2 Screening Evaluation ......................................................................................................22 2.3 Registration Procedures ..................................................................................................22 2.3.1 Treatment Assignment and Randomization/Stratification Procedures....................22 2.4 Baseline Evaluation.........................................................................................................23 2.4.1 Clinical Evaluation ..................................................................................................23 2.4.2 Laboratory studies ...................................................................................................23 2.4.3 Leukapheresis ..........................................................................................................24 3 STUDY IMPLEMENTATION .............................................................................................24 3.1 Study Design...................................................................................................................24 5 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 3.2 Administration ................................................................................................................25 3.3 Dose Modifications/Delays.............................................................................................26 3.3.1 Vaccine Dose Modification: None ..........................................................................26 3.3.2 Enzalutamide Dose Modification ............................................................................26 3.3.3 Criteria for individual patient re-treatment..............................................................26 3.4 Study Calendar................................................................................................................27 3.5 Cost and Compensation ..................................................................................................30 3.5.1 Costs ........................................................................................................................30 3.5.2 Compensation ..........................................................................................................30 3.5.3 Reimbursement ........................................................................................................30 3.6 Criteria for Removal from Protocol Therapy and Off Study Criteria.............................30 3.6.1 Criteria for removal from protocol therapy .............................................................30 3.6.2 Off-Study Criteria....................................................................................................30 3.7 Post-Study Evaluation.....................................................................................................31 3.8 Concomitant Treatment...................................................................................................31 3.8.1 Excluded medications..............................................................................................31 3.8.2 Treatment of vaccinia vaccination complication.....................................................31 3.8.3 Cidofovir (Vistide®, Gilead Sciences)....................................................................32 4 BIOSPECIMEN COLLECTION...........................................................................................32 4.1 Correlative Studies for Research.....................................................................................32 4.1.1 Parameters of Immune Response.............................................................................32 4.1.2 Immunological Assays.............................................................................................33 4.1.3 Additional Assays....................................................................................................35 4.1.4 Circulating Tumor Cells (CTC)...............................................................................35 4.1.5 Plasma VEGF levels ................................................................................................36 4.1.6 Serum analysis .........................................................................................................37 4.2 Adult patients: Blood Drawing Limits for Research Purposes .......................................37 4.3 Sample Storage, Tracking and Disposition.....................................................................37 4.3.1 Samples sent to Clinical Services Program (CSP) ..................................................37 4.3.2 Samples sent to Blood Processing Core (BPC) .......................................................38 4.3.3 Protocol Completion/Sample Destruction ...............................................................39 5 DATA COLLECTION AND EVALUATION .....................................................................39 6 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 5.1 Data Collection ...............................................................................................................39 5.2 Data Sharing Plans ..........................................................................................................41 5.2.1 Human Data Sharing Plan .......................................................................................41 5.3 Response Criteria ............................................................................................................41 5.3.1 Antitumor effect – Solid Tumors.............................................................................41 5.3.2 Definitions ...............................................................................................................42 5.3.3 Disease Parameters ..................................................................................................42 5.3.4 Methods for Disease Evaluation..............................................................................43 5.3.5 Response Criteria.....................................................................................................45 5.3.6 Duration of Response ..............................................................................................47 5.3.7 Time to Progression.................................................................................................48 5.4 Toxicity Criteria..............................................................................................................48 6 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....48 6.1 Definitions.......................................................................................................................48 6.2 OHSRP Office of Compliance and training/ IRB Reporting..........................................48 6.2.1 Expedited Reporting ................................................................................................48 6.2.2 IRB Requirements for PI Reporting at Continuing Review ....................................48 6.3 NCI Clinical Director Reporting.....................................................................................48 6.4 Institutional Biosafety Committee (IBC) Reporting Criteria..........................................48 6.4.1 Serious Adverse Event Reports to IBC ...................................................................48 6.4.2 Annual Reports to IBC ............................................................................................49 6.5 NIH Required Data and Safety Monitoring Plan ............................................................50 6.5.1 Principal Investigator/Research Team.....................................................................50 6.5.2 Safety Monitoring Committee (SMC) .....................................................................50 7 SPONSOR PROTOCOL SAFETY REPORTING................................................................50 7.1 Definitions.......................................................................................................................50 7.1.1 Adverse Event..........................................................................................................50 7.1.2 Serious Adverse Event (SAE) .................................................................................51 7.1.3 Life-threatening .......................................................................................................51 7.1.4 Severity ....................................................................................................................51 7.1.5 Relationship to Study Product .................................................................................51 7.2 Assessment of safety events............................................................................................52 7 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 7.3 Reporting of serious adverse events................................................................................52 7.4 Waiver of expedited reporting to CCR ...........................................................................52 7.5 Safety Reporting Criteria to the Pharmaceutical Collaborators......................................52 7.5.1 Reporting to Astellas ...............................................................................................52 7.5.2 Reporting to Bavarian Nordic, Inc...........................................................................53 7.6 Reporting Pregnancy.......................................................................................................53 7.6.1 Paternal Exposure ....................................................................................................53 7.7 Regulatory Reporting For Studies Conducted Under Ccr Sponsored Ind ......................54 7.8 Sponsor Protocol Deviation Reporting ...........................................................................54 8 CLINICAL MONITORING.................................................................................................54 9 STATISTICAL CONSIDERATIONS ..................................................................................55 9.1 Early Stopping Rule ........................................................................................................56 10 COLLABORATIVE AGREEMENTS..................................................................................56 10.1 Agreement Type..............................................................................................................56 10.1.1 Cooperative Research and Development Agreement (CRADA): ...........................56 10.1.2 Material Transfer Agreement ..................................................................................56 11 HUMAN SUBJECTS PROTECTIONS................................................................................56 11.1 Rationale for Subject Selection.......................................................................................56 11.1.1 Selection Based on Ethnicity, and Race ..................................................................56 11.1.2 Justification for Exclusions......................................................................................57 11.2 Participation of Children.................................................................................................57 11.3 Participation of Subjects unable to Give Consent...........................................................57 11.4 Evaluation of Benefits/Risks/Discomforts......................................................................57 11.4.1 Alternative Approaches or Treatments....................................................................57 11.4.2 Procedure for Protecting Against or Minimizing any Potential Risks ....................57 11.4.3 Provisions for Monitoring Data Collection to Ensure Safety of Subjects ...............57 11.5 Consent Process and Documentation..............................................................................58 11.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation...........................................................................................................................59 12 REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................59 12.1 Study Discontinuation and Closure.................................................................................59 12.2 Quality Assurance and Quality Control ..........................................................................59 8 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 12.3 Conflict of Interest Policy ...............................................................................................60 12.4 Confidentiality and Privacy ............................................................................................60 13 PHARMACEUTICAL INFORMATION .............................................................................61 13.1 Recombinant Fowlpox-PSA(L155)/TRICOM ............................................................61 13.1.1 Preparation, Handling and Disposal Recommendations .........................................62 13.1.2 Patient Care Implications and Contraindications ....................................................63 13.2 Recombinant Vaccinia-PSA(L155)/TRICOM ............................................................63 13.2.1 Classification ...........................................................................................................63 13.2.2 How Supplied ..........................................................................................................64 13.2.3 Preparation...............................................................................................................64 13.2.4 Storage .....................................................................................................................64 13.2.5 Stability....................................................................................................................64 13.2.6 Route of Administration ..........................................................................................64 13.2.7 Special Handling and Precautions ...........................................................................64 13.2.8 Preparation, Handling and Disposal Recommendations .........................................65 13.2.9 Precautions for Healthcare Workers........................................................................66 13.2.10 Recombinant Vaccinia Vaccine Patient Care Implications, Contraindications and Potential Complications.........................................................................................................67 13.2.11 Potential Complications Associated With Recombinant Vaccinia Vaccination .....68 13.2.12 Treatment of Vaccinia Vaccination Complications.................................................73 13.3 Cidofovir (Vistide®, Gilead Sciences) ...........................................................................74 13.4 Enzalutamide...................................................................................................................74 13.4.1 Description and formulation ....................................................................................74 13.4.2 Source ......................................................................................................................75 13.4.3 Storage .....................................................................................................................75 13.4.4 Stability....................................................................................................................75 13.4.5 Dosage and Administration .....................................................................................75 13.4.6 Adverse Effects:.......................................................................................................75 13.4.7 Drug Interactions .....................................................................................................76 14 REFERENCES ......................................................................................................................78 15 APPENDIX A: Performance Status Criteria .........................................................................82 16 APPENDIX B: Vaccinia-PSA(L155)/TRICOM Patient Instruction Sheet...........................83 9 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 17 APPENDIX C: Instructions for Pre-Study and Follow-Up Blood Tests...............................86 10 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 STATEMENT OF COMPLIANCE The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and the following: United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP Training. The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB) for review and approval.