Study personnel. 5.0 SAFETY MONITORING 5.1 Data Monitoring Committee (DMC) An independent Data Monitoring Committee will be established to ensure subject safety, to consider subject risks against the potential for meeting trial objectives, and to provide recommendations to BNI with respect to the conduct and analysis of the trial. The DMC will operate independently of BNI with the exception of the administration of compensation to the DMC members for DMC -related activities and non- voting activities such as clinical trial conduct updates. The voting members of the DMC will be a multi - disciplinary group that may include representative physicians who treat the type of subjects entered onto this tr ial; one or more individuals with statistical expertise; and if appropriate, one or more biological scientists. The DMC will meet either by phone or in person and will be provided with all available pertinent subject data in a manner specified in the approved Charter. An Executive Summary of Committee recommendations generated at each meeting will be forwarded to all IRBs/ECs as requested or required. Minutes of the closed sessions will be held in confidence by the DMC or its designee until the official close of the trial. The exact constitution and conduct of the DMC will be ultimately governed by the approved Charter. A vital status sweep will be performed in conjunction with each DMC meeting to ensure the most current data is being reviewed. 5.2 Dose- limiting Toxicities and Trial Stopping Rules 5.2.1 Dose- limiting Toxicities For the purposes of this trial, a dose- limiting toxicity (DLT) is defined as any anaphylactic reaction, a full - thickness ulceration/necrosis, or any AE ≥ Grade 3 definitely related to study drug with the following exceptions: Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 39 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. • Local injection site reactions lasting < 72 hours: pain, redness, swelling, induration, or pruritus • Systemic injection reactions lasting < 72 hours: fever ; myalgia, headache, nausea, fatigue Study drug should be discontinued for the subject in the case of a definitely related anaphylactic reaction or full -thickness ulceration/necrosis. Re- exposure to study drug after development of other related AE ≥ Grade 3 should only occur if the event resolved or is reduced to grade 1 tox icity. 5.2.2 Trial Stopping Rules In the event of a death definitely related to study drug within 24 hours of vaccination or ≥ 3 definitely related SAEs (per 20 patients) at any time after receiving study drug during the treatment period, dosing will halt immediately and the DMC will be consulted. All data will be reviewed prior to any further dosing, and dosing will not continue until the DMC agrees that it is safe to continue. At the discretion of the DMC, the FDA or other Health Regulatory Agencies may be consulted. The decision to permanently halt the trial may only be made by BNI Executive Committee. 5.3 Emergency Unblinding Of Treatment Assignment (If Applicable) All investigational vaccine products for this study have been packaged and labeled in a blinded fashion. GM-CSF will be labeled for investigational use as required by the local and regional Health Authorities, Lyophilized GM- CSF is not packaged and labeled in a blinded fashion. Reconstituted GM- CSF or GM - CSF placebo in single- use syringes is blinded. Unblinding by study site personnel for adverse events should only be performed in emergencies where knowledge of the subject’s treatment assignment is essential for further management of the subject’s medical care. Unblinding a subject’s treatment assignment under any other circumstances will be considered a protocol violation. The Principal Investigator is strongly encouraged to contact the BNI Medical Monitor before unblinding any subject’s treatment assignment, but must at least do so within 1 working day after the unblinding. Although the Medical Monitor should be contacted the subject’s treatment code should not be communicated to the Medical Monitor. Emergency unblinding for adverse events will be performed through an interactive voice-response system (IVRS). All calls resulting in an unblinding event are recorded and reported by the IVRS. Emergency unblinding must also be documented at the study site. The Medical Monitor will receive notification of unblinding from IVRS but will not be notified of the subject’s treatment assignment. 5.4 Removal of Subjects from Therapy or Assessment Subjects may withdraw consent for participation in the study at any time without prejudice. Additionally, the investigator may withdraw a subject if, in his/her clinical judgment, it is in the best interest of the subject or if the subject cannot or will not comply with the protocol. Wherever possible, the End- of-Study tests and evaluations listed in Section 7.4 should be carried out at the time the subject withdraws or whenever the Investigator feels that the subject will be unable to make any further visits. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 40 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. If a subject fails to return for the necessary visits or discontinues prematurely from the study, a genuine effort must be made to determine the reason why. If the subject or his designated contact is unreachable by te lephone, the minimum of a registered letter should be sent requesting that contact be made with the Investigator (or designee) to report survival information. Every attempt possible to obtain follow -up blood samples for safety and immune monitoring should be made. Request for an autopsy, autopsy report and death certificate when/if the subject expires while on trial should be pursued. BNI may discontinue individual subjects, study arms, individual study centers, or the entire study at any time provided sufficient time is given to ensure subject safety. 5.4.1 Clinical or Kinetic Progression: Removal of Subjects from Therapy Subjects who experience a significant clinical progression during the treatment phase (i.e., before last vaccination is received) will be counseled to seek alternative therapy. Significant clinical progression is defined by the need to institute scheduled narcotic pain relief measures for cancer -related pain, or acceleration of tumor growth kinetics by PSA (PSA doubling time <1 month). Such subjects are allowed to continue vaccine therapy at the discretion of the PI if the decision is made not to seek alternative anti - cancer treatment(s). If subjects choose to initiate alternative anti -cancer treatment, vaccination will be discontinued. All subjects will continue on study and will be followed for survival and safety per protocol. 5.4.2 Biochemical or Radiological Progression: Continuation of Therapy Vaccination may take several months to induce an immune response. PSA declines and radiological respons es are infrequent, and the expectation is for a slowing of ongoing disease progression. Due to the delayed effect of vaccine induced immunotherapy, PSA progression and radiological progression may be expected during the treatment phase of the trial, and are not a cause for stopping vaccination. Continued vaccination to maximize immune response is believed to be beneficial based on earlier clinical trials. 5.5 Replacement Policy 5.5.1 Subjects No subjects will be replaced in this study. All subjects who receive at least one dose of PROSTVAC -V/F or placebo will be considered evaluable and will be included in all appropriate analyses as described in Sectio n 9.0. 5.5.2 Research Centers Centers will be opened only after all requirements for documentation have been met as defined by Appendix M (M-I-C- 1) of the NIH Guidelines for Research Involving Recombinant DNA Molecules (April 2002) or the appropriate regional or national guidelines outside the United States. If an approved institution declines further participation or is dropped for any reason, or if enrollment lags, new centers may be added under the same restrictions. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 41 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 6.0 STUDY TREATMENTS 6.1 Investigational Study Drug Accountability Prior to study start, each Investigator will provide the actual location (facility, room number, and freezer/refrigerator number, if any) and identify the pharmacist, study coordinator, sub- investigators, or other personnel who will have access to the drug, and if different from above, any personnel who will have preparation, administration, receipt and disposal responsibilities of the study drug. It should be noted that reco nciliation of PROSTVAC -V/F and GM -CSF vials will be performed by an independent unblinded monitor in order to keep the study monitor blinded. Accurate records of dates, quantities and the lot or vial numbers of all study drug received, to whom dispensed ( subject -by-subject accounting), and accounts of any product accidentally wasted or intentionally disposed of must be maintained. The disposal of all used, partially used, or wasted study drug vials and syringes must be performed in accordance with the hospital or institution’s drug disposal policy for infectious medical waste. Used vials will not be retained by the pharmacy for drug accountability. The institution’s policy for disposal must be kept in the Pharmacy Manual and a copy provided to BNI. Accountability records must be maintained and readily available for inspection by representatives of BNI or designee and are open to inspection by regulatory authorities at any time. 6.2 Assessment of Study Drug Compliance Accountability and reconciliation of drug dispensing and administration compliance will be assessed by review of adequate drug dispensing (including return) records performed periodically by the unblinded monitor . A drug dispensing log must be kept current and will be reviewed periodically throughout the study by the unblinded monitor. 6.3 Disposal of Drug Supplies Local or institutional regulations require immediate disposal of used study drug. The investigational site staff is to destroy any dispensed study drug vials and syringes in accordance with the institution’s policy. Source document verification will be performed on the remaining inventory and reconciled against the documentation of quantity shipped, dispensed, and disposed. Each research center must provide BNI a statement of the institutional policy and procedures for disposing of material with a Biosafety rating of RG2 ( Appendix 14.2; RAC Guidelines 2002, Appendix B or equivalent outside the United States) and the institution’s policy and procedures for disposal of hazardous waste or biologic products. A copy of the policy must be placed in the Pharmacy Manual and provided to BNI. At the conclusion of the Treatment phase of the study, all unused vaccine, GM- CSF, and placebo supplies (collectively, study medication) will be either disposed of on site or by a licensed facility Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 42 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. contracted by the site following final reconciliation. Subjects who received home- injections will be instructed to return all used and unused GM- CSF syringes to the site for disposal (n ot applicable to subjects enrolled in France as they must return to the clinic to receive GM- CSF injections) . BNI or its designee will provide logs to each site pharmacy for recording IP dispensing (subject ID, date, disposal, etc.). Sites may use their own logs provided the required data is adequately captured. 6.4 PROSTVAC -V/F PROSTVAC -V is considered a BSL- 2 agent; PROSTVAC -F is con sidered BSL- 1 (but may be considered BSL-2 outside the United States, depending on country specific requirements). All vaccines in this trial should be handled using standard infection control procedures and study staff should wear personal protection consisting of at least a lab coat, gloves, and protective eyewear when handling PROSTVAC -V/F. More complete instructions and guidelines are included in the Study Instruction Manual and Pharmacy Manual. PROSTVAC -V/F is prepared in a phosphate- buffered saline (PBS) with 10% glycerol and stored at - 70˚C or colder until the day of use. Once used and accounted for, vials should be disposed of according to institutional standards, local and occupational safety guidelines. There is no pre- treatment regimen for PROSTVAC -V/F. PROSTVAC -V/F should not be mixed wit h any other medicinal product . Refer to the pharmacy manual for instructions regarding administration. Subjects should remain in the clinic for at least 30 minutes following administration of PROSTVAC -V/F or placebo for observation for signs of adverse reactions. 6.5 GM-CSF GM-CSF (sargramostim; Leukine ®) is a glycosylated, recombinant human GM- CSF manufactured by Genzyme Corporation. GM- CSF is an altered form of the native molecule; the position 23 arginine has been replaced with a leucine to facilitate expression. Leukine is preserved with benzyl alcohol and provided in vials containing 250 μg of lyophilized product. GM- CSF is reconstituted using USP bacteriostatic water for injection (1.0 ml per vial). Refer to the Pharmacy Manual for instructions regarding administration). If the subject or their caregiver is proficient at self injection (as determined by the study staff) , (s)he may be provided with the pre- filled syringes of GM- CSF (or placebo) for self injection for each of 3 consecutive days following the day of vaccination. If the subject or their caregiver is unable or does not wish to self inject, the subject must return to the clinic for three consecutive days following the vaccination to receive the GM- CSF or placebo (s ubjects enrolled in France must return to the clinic for three consecutive days following the vaccination to receive GM- CSF or placebo) . Protocol BNIT -PRV-301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 43 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. Site personnel are instructed to query subjects self -injecting GM -CSF for compliance and record the outcome in the subject’s chart. 6.6 Subject Instructions and Supplies Subjects, and if possible, subject caregivers, should be educated as to the care of the injection site, including proper bandage changing, bathing, possible side effects, and minimization of contact with at -risk individuals. Subjects will be provided with injection site care ‘kits’ containing, for example; instruction sheets, disposable gloves, absorbent toweling, alcohol swabs, non -adherent Telfa -type bandages, band - aids, zip -lock biohazard bags for disposal of used bandages and gloves , pre-filled syringes for home injection of GM -CSF or placebo, a cold pack, a sharps container, and contact information for the study personnel (not applicable to subjects enrolled in as they must return to the clinic to receive GM - CSF injections) . Subjects should be instructed to return the zip -lock biohazard bag containing all used supplies at their next clinic visit. 6.7 Dose Reductions and Contraindications for PROSTVAC -V/F There are no dose reductions for this study. Subjects who experience intolerable reactions will be discontinued from treatment but will remain on study and be followed for safety, immune status, and survival per protocol. PROSTVAC -V/F will be discontinued as defined in Section 5.4. Subjects discontinued from further vaccination should remain on study and continue to be followed for safety, immune status, and survival per protocol. For acute illnesses (fever, infectious disease, respiratory insufficiency, chest pain, angina, etc.) present at the time of a scheduled vaccination, the vaccination can be delayed until symptoms subside, the underlying process is treated or resolves, or the subject may be withdrawn at the discretion of the Investigator. If vaccinations are delayed due to acute illness, timing for scheduled assessments and remaining vaccinations should be reestablished according to the original Schedule of Events (Appendix 14.1) as soon as possible. 6.8 Procedures for Potential Serious Vaccinia Reaction The Investigator must notify an Infectious Disease Specialist in the Pharmacovigilance Group (PVG) if there is a suspected serious vaccinia reaction as soon as possible, but no later than 24 hours after he/she becomes aware. The Investigator should contact the BNI study Medical Monitor if there are specific questions in regard to the potential vaccinia reaction. A swab of the suspected lesion may be obtained from the study subject for confirmatory testing prior to administration of VIG. The Investigator should refer to the Management Plan for Potential Serious Vaccinia Reaction for recognition, diagnosis and treatment of a rare potential serious vaccinia reaction. This plan also describes when VIG is indicated for use and administration procedures. For further information or for a supply of VIG in the United States, contact the Centers for Disease Control at (877) 554 -4625. For centers outside the United States, VIG suppliers (where known) are listed in the Study Instruction Manual. The Investigator should refer to the Management Plan for Potential Serious Vaccinia Reaction . If VIG treatment is warranted, the Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 44 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. person receiving VIG must sign the Consent Form to Administer Vaccinia Immune Globulin (VIG) PRIOR to administration of VIG. 6.9 Concomitant and Excluded Medicati ons 6.9.1 Concomitant Medications: Subjects will be on concomitant androgen suppression therapy with a GnRH agonist or antagonist, unless surgically castrated. Subjects may also be on concomitant drugs to prevent bone loss or skeletal -related events, including bisphosphonates and denosumab. Subjects may receive palliative radiotherapy during the trial. 6.9.2 Excluded Medications: During the Treatment phase of the study (approximately 5 months) all medications required for the health of the subject are allowed with the following exceptions: • Concurrent chemotherapy • Concurrent immunotherapy (e.g. sipuleucel -T, etc.) or immunosuppressive therapy (e.g. etanercept, natalizumab, etc.) • Concurrent anti -cancer radionuclides • Concurrent systemic corticosteroid use (daily or every other day for continued use > 14 days) • Concomitant use of secondary anti -cancer hormonal treatments (e.g. abiraterone) 6.10 Overdose Because PROSTVAC -V and PROSTVAC -F are provided in single- dose vials there is no potential for an overdose. The highest single dose of PROSTVAC -V (2x10 8 Inf. U.) or PROSTVAC -F (1x109 Inf. U.) used in human studies did not show any dose- limiting toxicity. Because the GM- CSF dose on this study is approximately five times lower than the approved therapeutic dose, there is no potential for an overdose. Possible side effects with the use of standard dosage are described in the commercial product insert (see the Pharmacy Manual). Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 45 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 7.0 STUDY PROCEDURES BY STUDY PERIOD 7.1 Screening Assessments (Days –28 –1) Screening activities must be completed within 28 days prior to the first dose of any study medication unless noted. Assessments will be done over one or more visits and are to be completed prior to dosing. Subjects requiring anti- androgen wash- out specifically for this protocol should be consented prior to beginning withdrawal of therapy. No other screening procedures should be performed until it is clear that the subject is eligible as defined in Sections 4.6 and 4.7. Subjects requiring wash- out and re- testing will be asked to re- sign an informed consent form prior to any additional screening procedures. Screening assessments performed greater than 28 days prior to first dose will need to be repeated except as specified below. Subjects must be entered into IVRS after signing Informed Consent and prior to any screening procedures being initiated. For the purposes of this trial, one month = 4 weeks = 28 ± 3 days. After signing the Informed Consent, Screening assessments will include: 1. Complete medical history, including smallpox vaccination history 2. Prostate cancer history (primary diagnosis, progression history, treatments received; procedures undergone) 3. Concomitant medications (all drugs currently being taken, all drugs prescribed during the past month, and all over -the-counter drugs or supplements (excluding vitamins) taken for ≥5 consecutive days during the past month) 4. Complete physical examination (PE) including vital signs (VS; sitting blood pressure [BP], heart rate, respiration rate [RR]), temperature, height and weight 5. ECOG performance status 6. 12-lead E CG 7. Blood samples will be obtained for: a. Hematology (CBC and differential, RBC with indices, platelet count). b. Serum chemistry (BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, LDH, sodium, potassium, chloride, bicarbonate, calcium and glucose). c. Testosterone level. d. C-reactive protein. e. Cardiac markers (CK, CK- MB, Troponin T and I). f. Coagulati on panel (PT (INR)/PTT). g. Serum PSA and PAP (prostatic acid phosphatase) levels. Protocol BNIT -PRV - 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 46 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. h.