(vaccinia) or 6 x 109 Inf. U. (fowlpox); (b) vaccinia- based and fowlpox -based vaccines containing costimulatory molecules, alone or in combination with CEA or PSA antigens, administered without serious adverse effects, as outlined below. Poxviral vectors containing PSA, either alone or with B7.1 or TRICOM, have been evaluated in 13 different Phase 1 (5 trials) and 2 (8 trials) comprising over 400 vaccinated subjects with advanced prostate cancer. In addition, there are three other fully enrolled, and two open studies using PROSTVAC - V/F treatment, for an additional 100 treated subjects. There have only been two serious adverse events thought to be possibly due to the PROSTVAC -V/F treatment (both in the same subject): the subject had a myocardial infarction and it was found that he had Grade 4 thrombotic thrombocytopenic purpura, thought to be possibly related to study drug, approximately 3.5 weeks after receiving the fourth dose of his vaccine. This resolved with therapeutic apheresis treatment, however, the subject continued to do poor ly (for a more detailed description of this case, see Investigator’s Brochure). Thrombotic thrombocytopenic purpura has not been reported as an adverse event in large scale studies of smallpox vaccination with vaccinia. 1.5 Safety of Poxviral Vectors 1.5.1 Vaccinia Virus Vaccinia virus causes a transient infection, with elimination of viral components over several weeks. Host cells infected with vaccinia virus are short lived (days) and die by a mixed form of apoptosis/necrosis. Vaccinia replicates in the cytoplasm of infected cells, and viral DNA does not integrate into the host cell DNA. Vaccinia virus is known to be shed from the wound site in traditional dermal scarification based vaccination. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 25 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. The use of vaccinia virus for worldwide eradication of smallpox provides a safety database with number of observations in the millions. Geographical differences in strains of vaccinia virus used as well as differences in reporting practices, diagnostic and follow -up criteria between countries are a cause of some discrepanc ies in the incidences of adverse events reported, but the overall picture of vaccinia virus safety is very well known. An additional set of data is provided by recent vaccination campaign of military and civilian vaccinations in the US. A number of events post vaccination are expected and considered to be normal: fever, myalgia, headache, fatigue, chills, nausea, soreness and erythema at the vaccination site, local lymphadenopathy. Satellite lesions around the vaccination site have been reported as well as local edema. These symptoms are self -limiting, last for around three weeks after vaccination and rarely are a cause for serious concern (Frey 2002, Fulginiti 2003). Mild adverse reactions that can occur post vaccination are bacterial superinfection of vaccination site, erythema multiforme (EM) and generalized vaccinia. Superinfection is a rare event with incidence from 0.14 to 55 cases per million according to different reports (Vellozzi 2004). EM most often presents as papules, plaques or urticaria which may be symmetrical, may involve palms and soles. EM resolves spontaneously and requires no special care. A development of Stevens -Johnson syndrome with mucosal involvement is extremely rare, with only one case noted in the 2003- 2004 vaccination campaign in the US (<1 per 1,000,000) (Fulginiti 2003, Neff 2008). Generalized vaccinia results from viremic spread of vaccinia virus from the vaccination site. It presents as a generalized rash, which behaves like the vaccination site lesion, progressing through papular, vesicular, pustular and scab- forming stages. The incidence is difficult to assess, since historically there was no strict definition to distinguish generalized vaccinia from other conditions where rash is a dominant symptom (severe chickenpox, smallpox, eczema vaccinatum, EM). Retrospective analysis of 2002 – 2004 vaccinations suggests an incidence of ~50 cases per 1,000,000 (Bryant -Genevier 2006). The rash appears within a week after vaccination and resolves within a week. Most instances do not require specific therapy (Fulginiti 2003). Some of the post -vaccinia adverse events, although very rare, are serious and potentially life- threatening. They are described as follows. Progressive vaccinia (PV) is the most serious complication known. It was almost always fatal prior to the introduction of vaccinia immune globulin (VIG). PV occurs predominantly in persons with T -cell deficiencies or receiving treatments that result in T -cell deficiencies. The primary vaccination site fails to heal leading to a severe local reaction with necrosis, and viremic spread of vaccinia leads to generalized appearance of new lesions without reactive immunoinflammatory response (Bray 2003, Fulginiti 2003). PV is extremely rare; historical incidence is in the order of 1 case per 1,000,000. There were no reports of PV in the military and civilian vaccines in 2002 – 2004 vaccination campaigns (Neff 2008). Eczema vaccinatum (EV) manifests as rash ( papular , vesicular, pustular, erosive) that can be localized or generalized and predominantly occurs in the areas that have been affected by lesions of atopic dermatitis or other eczematous skin condition. Historically it occurred at a rate of ~1 case per 25,000 vaccinations. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 26 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. EV can occur in a vaccine recipient as well as in susceptible individuals in close contact. Two cases of EV from transmission have been recently reported both in children of recently vaccinated US military personnel (Lederman 2008, Vora 2008) . In the military vaccination program in the US there were no reports of EV among 450,239 vaccinees, probably due to careful screening for contraindications (Grabenstein 2003). Review of civilian vaccinations did not detect any cases of EV (Velozzi 2004). EV can be prevented by thorough screening of at -risk individuals and education on importance of avoiding contacts with such persons and proper hygiene. Postvaccinial encephalitis (PVE) historical case -fatality rate is 25%. The historical (1963 – 1968) reported frequency of PVE in United States was reported at 2.9 cases per 1,000,000 (Aragon 2003). PVE has higher prevalence and mortality rate in children compared to adults. Higher historical rates were reported in Europe compared to United States. Variability is attributed to differences in case definitions, clinical evaluations and differences in vaccine strains used by different countries (Sejvar 2005). Pathogenesis is still under investigation, although several compelling theories focus on autoimmune mechanism. Aside from vaccinia, measles and rabies vaccines have known association with PVE, as well as other viral and bacterial infections (Benneto 2004, Menge 2007). Review of 2002 – 2004 vaccinations in US reported three cases of PVE for the rate of 5 per 1,000,000. Recent vaccination campaign in the US revealed a higher than historically observed incidence of myo/pericarditis in vaccinees. Predominant symptoms were chest pain, shortness of breath and fatigue, typically mild and transient. Among military contingent, 88% of cases occurred in men with the incidence of 16.11 per 100,000 for primary vaccines and 2.07 per 100,000 in revaccinees (Arness 2004). In civilian population women accounted for 67% of cases and the majority of events (86%) were reported i n revaccinees (Casey 2005, Sniadack 2008). Variability between the two sets of data may be explained by differences in demographics of vaccinees, case detection, ascertainment and reporting practices (Morgan 2008). Myo/pericarditis has been long associated with a number of viral infections, although there are very few reports of confirmed viremia. A few cases of myo/pericarditis have been reported following DTP and influenza vaccinations (de Meester 2000, Boccara 2001). It is currently assumed that injury to the heart post viral infection is more of an immune inflammatory than direct nature (Cassimatis 2004, Feldman 2000). Review of data from 2002 – 2004 vaccinations in US reported ~1 case of autoinoculation per 6,500 vaccinations with 17% of ocular cases, none with corneal involvement (Neff 2008). Vaccinia keratitis is the most serious consequence of autoinoculation, since lesions on the cornea threaten eyesight. Diseased or injured conjunctiva and cornea may increase the risk of this complication. Vaccinia keratitis will respond to treatment with topical antiviral agents and interferon and can be prevented with use of occlusive bandages over the scarification site and by subject education (Fulginiti 2003). Transmission of vaccinia to close contacts is another known complication. Contact vaccinia may manifest as progressive vaccinia, eczema vaccinatum or accidental infection of eye, mouth, genital areas. Review of several national and state surveys between 1962 and 1968 gives frequency for EV at 8 - 27 per Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 27 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 1,000,000 and for accidental infections at 3 - 44 per 1,000,000 (Neff, 2002). The rate of contact vaccinia in 2002 – 2004 was <10 cases per 100,000. Education of vaccinees in proper care for the vaccination site, proper hand hygiene and avoidance of contact with at risk individuals seems to be a reasonable and effective prophylactic against contact vaccinia. PROSTVAC -V/F immunization is subcutaneously administered, which greatly reduces injection site reactions, and skin surface wound formation/viral shed ding. PROSTVAC -V/F is also given to vaccinia pre- immune persons. Both of these factors reduce the potential for inadvertent infection versus traditional smallpox vaccine programs. 1.5.2 Fowlpox Virus Fowlpox virus has been investigated and used in vaccine design for at least two decades. As a pox virus, it offers the advantages of a large genome but provides an additional safety assurance by not being able to replicate in mammalian cells. Fowlpox virus -based vaccines have been tested in both animals and humans for HIV, malaria and cancer. No safety concerns have been raised and the adverse events associated with the use of fowlpox vector have been limited to mild injection site reactions (Beukema 2006, Webster 2006). 1.6 Potential Benefits and Risks to Human Subjects The intent of vaccination with PROSTVAC -V/F is to induce an immune response to prostate- specific antigen (PSA), and other prostate- and tumor -specific antigens. In the randomized, placebo controlled Phase 2 trial ; an over -all survival benefit among patients who received PROSTVAC -V/F was observed. It is unknown whether PROSTVAC -V/F will provide this benefit to subjects participating in this trial, as this product is still currently in development. Benefits of this trial also include the potential boosting (or acquisition) of protective immunity against smallpox. Based on clinical experience with PROSTVAC -V/F in Phase 2, adverse reactions are expected to be minimal. A local injection site reaction is typical, and comparable to those seen with other modern vaccines. Potential adverse reactions attributable to the administration of PROSTVAC -V/F at ≥ 50% frequency include injection site reactions (pain, swelling, induration, and redness), and at ≥ 10% frequency include headache, fatigue, myalgia, and nausea; the majority of events of Grade 1 and 2 in severity. The priming vaccination with PROSTVAC -V is with a vaccinia- based replicating virus. Special wound precautions are required. The vaccinia virus has been used in millions of people to eliminate smallpox. In this trial it is given subcutaneously, not by dermal scarification, and local injection site reactions are much less severe, and viral shedding is minimal. However, there are still risks of inadvertent infection of other body sites (through scratching), or transfer of infection to others. Special bandage precautions are required, and subjects need to avoid contact with small children <3 years of age, individuals who are immunocompromised or are receiving immunosuppressive therapies, and pregnant or lactating women Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 28 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. (for 3 -4 weeks). With smallpox vaccine programs in vaccinia- naïve subjects immunized by dermal scarification, inadvertent inoculation occurred approximately 1/6,000 vaccinations. Subjects in this trial wil l be given detailed instructions on proper care of the injection site and rules of hygiene to prevent inadvertent inoculations and transmission of vaccinia virus. In the recent series of military and civilian vaccinations, vaccinia immunization has been reported to induce myopericarditis. Symptoms of chest pain were typically mild and transient, but occurred in 1/1,000 subjects. The incidence of this complication is lower in re- vaccinees. To prevent potential exacerbation of existing chronic problems, this protocol excludes subjects with known history of heart disease from participating in the trial. In addition, there are rare risks of severe and possibly life- threatening adverse reactions. These include eczema vaccinatum (~1/25,000, usually with history of underlying skin disorder) or progressive vaccinia infections (~1/300,000, usually with underlying immunodeficiency), or post vaccinial encephalitis (~1/500,000, usually infants or small children). These were observed after the administration of conventional smallpox vaccines, and have not been seen in prior studies of PROSTVAC -V/F or related PSA (or other tumor antigen- containing vaccinia virus vaccines) administered to vaccinia pre- immune cancer subjects Under the proposed protocol, age restriction, exclusion of all pre- existing conditions with features of immune suppression and skin disorders minimize the risk of such rare complications. During study treatments, subjects will be under the continuous care of the investigator and his/her staff and will be assessed for adverse events which will be recorded in the subject’s CRF. SAEs must be reported to BNI or its designee within 24 hours of discovery. To minimize risk, potential subjects who have a known allergy to eggs, egg products, aminoglycoside antibiot ics or GM -CSF, or other pre- existing medical conditions known to be risk factors for SAEs will be excluded from participation. In view of the anticipated mild side effects, the potential risks for the subject seem to be limited and to justify the potential benefit of participating in this trial. 1.7 Rationale for Double -Blinding This study has been designed to be double- blinded despite having an objectively ascertained primary endpoint (survival) for the following reasons: • There will be no study defections due to randomization disappointment (so subjects randomized to placebo will not quit the study). • There will be no difference in use of post-treatment anti-cancer therapies or concomitant therapies due to knowing the intervention being delivered. • There will be no difference in the interpretation of biomarkers or lab tests due to knowing the intervention being delivered. • The between- arm comparison of adverse events will not be corrupted by knowing the intervention being delivered. Protocol BNIT -PRV-301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 29 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 2.0 NAME AND DESCRIPTION OF STUDY AGENTS 2.1 Formulation, Packaging, and Labeling The PROSTVAC -V/F study vaccines, including placebo, are manufactured at in compliance with current good manufacturing practices (cGMPs). The formulations do not contain adjuvants or preservatives. the vials are sealed with rubber injection stoppers and plastic/aluminum flip -caps, and a label is affixed to the vial. PROSTVAC -V/F study vaccine vials are then packaged in 6 -vial cartons with an outer carton label . GM-CSF (Leukine®: 250 μg, lyophilized) will be purchased from licens ed, US pharmacy wholesalers. Lyophilized GM -CSF is reconstituted with 1.0 mL bacteriostatic water for injection. GM -CSF vials will not be relab eled, and will be packaged in 5 -vial cartons with an outer carton label . GM-CSF placebo is bacteriostatic sodium chloride for injection and will be purchased from licensed, US pharmacy wholesalers. GM -CSF placebo vials will not be relabeled, and will be packaged in 25 -vial trays with a label . Examples of carton and vial labels are included in Appendix 14.10. 2.2 Investigational Drug Product (PROSTVAC -V/F) PROSTVAC -V/F is comprised of two components. PROSTVAC -V is a replication -competent vaccinia virus which has been engineered to encode the sequences for a modified human prostate -specific antigen (PSA) and a triad of co -stimulatory molecules (TRICOM). PROSTVAC -F is a fowlpox virus which does not replicate in human cells and has been engineered to encode the same sequences present in PROSTVAC -V. A full description of the PROSTVAC -V/F product and PROSTVAC -V/F pre-clinical and clinical support are contained in the Investigator’s Brochure. Study vaccine for this trial contains no preservatives or adjuvants and is supplied in single -dose 2 ml clear, borosilicate glass injection vials with rubber injection stoppers covered by a plastic -aluminum flip cap. Active Ingredient: PROSTVAC -V: PROSTVAC -V-PSA-TRICOM in aqueous solution for injection PROSTVAC -F: PROSTVAC -F-PSA-TRICOM in aqueous solution for injection Product Descr iption: PROSTVAC -V/F is comprised of two recombinant pox viruses: a recombinant vaccinia virus (PROSTVAC -V) and a recombinant fowlpox virus (PROSTVAC -F). Protocol BNIT -PRV - 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 30 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. Dose: 0.5 ml containing at least 2 x 108 Infectious Units (Inf.U) PROSTVAC -V 0.5 ml containing at least 1 x 109 Inf.U PROSTVAC -F Route of Administration: Subcutaneous injection Storage*: −70°C or below There is no pre - treatment regimen for PROSTVAC -V/F. * Storage conditions and stability claims for the final PROSTVAC -V/F product are based on long - term manufacturing experience with PROSTVAC -V/F by Therion, the initial manufacturer. The stability data for PROSTVAC -V/F shows virus titer stability for four years when stored at −80°C (± 10°C). Regimen of Administration: Doses of PROSTVAC -V/F or placebo will be drawn into labeled syringes by an independent, unblinded research pharmacist or designee for use by the clinic staff. PROSTVAC -V will be administered by the study staff once by sc injection on one side (upper arm or upper outer thigh) during Week 1. PROSTVAC -F will be administered by the study staff six times by sc injection during Weeks 3, 5, 9, 13, 17, and 21. Vaccination with PROSTVAC -F will begin on one side (upper arm or upper outer thigh), and subsequent immunization sites should be rotated to the opposite side and/or limb if possible. 2.3 GM-CSF GM-CSF (Leukine®: 250 μg, lyophilized) will be purchased from licensed, US pharmacy wholesalers and labeled appropriately for the study. Lyophilized GM -CSF will be reconstituted using 1.0 ml of room temperature bacteriostatic water for injection (USP -grade or equivalent). Product reconstituted with bacteriostatic water for injection is stable for 20 days if stored between 2 and 8°C in the original vial. See product label for information related to product description and formulation. Doses of GM - CSF of 100 μg each will be drawn into labeled syringes by an independent, unblinded research pharmacist or designee for use by the clinic staff or by individual subjects for home injectio n (s ubjects enrolled in France must return to the clinic to receive GM - CSF injections) . Dose: 0.40 ml (100 μg) GM - CSF Route of administration: Subcutaneous injection Storage: 2 - 8°C (lyophilized and reconstituted); Up to 4 days at 2 - 8°C when in syringes Regimen of administration: GM-CSF will be injected sc by the study staff on the day of vaccine or placebo administration and for the subsequent 3 days, within approximately 5 mm of the injection site by the study staff, the subject, or subject’s caregiver (subjects enrolled in France must return to the clinic to receive GM -CSF injections) . Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 31 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 2.4 PROSTVAC -V/F Placebo : Empty fowlpox vector The PROSTVAC -V/F placebo will be provided in blinded vials matched to active product. The same placebo will be used for both vaccinia and fowlpox PROSTVAC -V/F components. Dose: 0.5 ml containing at least 1 x 109 Inf.U Route of administration: Subcutaneous injection Storage: –70˚C or below Regimen of administration: PROSTVAC -V placebo will be administered once by sc injection by the study staff in the upper arm or upper outer thigh during Week 1. PROSTVAC -F placebo will be administered by the study staff six times by sc injection during Weeks 3, 5, 9, 13, 17, and 21. Vaccination with PROSTVAC -F placebo will begin on one side (upper arm or upper outer thigh), and subsequent immunization sites should be rotated to the opposite side and/or limb if possible. 2.5 GM-CSF Placebo GM-CSF placebo will consist of USP- grade or equivalent bacteriostatic sodium chloride (saline) for injection. Doses of GM- CSF placebo will be drawn into labeled syringes by an independent, unblinded research pharmacist or designee for use by the clinic staff or by individual subjects for home injection (subjects enrolled in France must return to the clinic to receive GM- CSF placebo injections) . Dose: 0.40 ml injection of bacteriostatic sodium chloride (saline) for injection Route of administration: Subcutaneous injection Storage: Room temperature when in vials; Up to 4 days at 2-80 C when in syringes Regimen of administration: GM-CSF placebo will be administered sc on the day of PROSTVAC -V/F or PROSTVAC -V/F placebo vaccination by the study staff and for the subsequent 3 days, within approximately 5 mm of the PROSTVAC -V/F or PROSTVAC -V/F placebo vaccination site by the study staff, the subject, or the subject’s caregiver (subjects enrolled in France must return to the clinic to receive GM- CSF p lacebo injections) . Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 32 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 3.0 STUDY OBJECTIVES AND ENDPOINTS 3.1 Study Objectives 3.1.1 Primary Efficacy Objective To ascertain whether the survival of subjects randomized to Arm V+G (PROSTVAC -V/F plus GM- CSF) or to Arm V (PROSTVAC -V/F) is superior to that from subjects randomized to Arm P (placebo control). 3.1.2 Secondary Efficacy Objective To ascertain whether a greater proportion of subjects randomized to Arm V+G or to Arm V remain event - free at six months (or early termination) as compared to the subjects randomized to Arm P. 3.1.2.1 Definition of Event (To be Used in Secondary Endpoint) Progression events will be defined as: • Radiographic progression o Two new lesions on bone scan, new metastases on CT scans *, or an increase size of nodal lesions per RECIST 1.1. • Pain progression o Introduction of scheduled opioid narcotics for cancer -related pain control. • Initiation of chemotherapy • Death * For subjects with allergies to contrast agents, MRIs for abdomen and pelvis may be performed. Only in cases where MRI is unavailable may a non- contrast CT be performed. For subjects enrolled in Germany, MRI must be used as the primary imaging modality. Radiographic progression will be assessed by bone scan at 3 and 6 months, and by CT scan ( or MRI for subjects in Germany) at 6 months (and at the time of progression, or any time during the treatment period if clinically indicated). For secondary endpoint analysis, baseline scans and 6 month scans (or early termination scans) will be compared by central radiology review. Bone scan and CT (or MRI for subjects in Germany) data will be archived up to five years past the end of the trial. In addition, for an exploratory endpoint, we will assess radiological progression at 12 months (6 months post End- of-Treatment visit) by comparison with the 6 month scans (from End- of-Treatment visit or early termination). This will attempt to define effects on secondary progression, and characterize delayed effects of investigational vaccine therapy. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 33 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 3.1.3 Safety Objective To further characterize the safety and tolerability of PROSTVAC -V/F immunotherapy, characterize type and number of AEs compared to placebo. 3.1.4 Exploratory Objectives To model secondary radiological disease progression over the first year of study participation. To ascertain whether a greater prop ortion of subjects randomized to either Arm V+G or Arm V remain event -free (radiological progression) six months post End- of-Treatment visit (using scans at End- of- Treatment visit as a new baseline), as compared to the subjects randomized to Arm P. This a nalysis will include all subjects, and separately the HLA -A2-expressing subgroup. To assess the role of post -treatment anti-cancer therapies as an alternative explanation for observed survival differences. To ascertain whether the survival of HLA -A2-expressing subjects randomized to Arm V+G, or Arm V is superior to that from HLA -A2-expressing- subjects randomized to Arm P. To ascertain whether a greater proportion of HLA -A2 expressing subjects randomized to Arm V+G or to Arm V remain event -free at six months as compared to the HLA -A2 expressing subjects randomized to Arm P. To compare arms with respect to immune response to immunizing antigen (PSA), as well as to non- vaccine containing prostate antigens, and tumor -associated antigens, and assess whether immune responses are prognostic and/or predictive. To evaluate for baseline biomarkers which are prognostic and/or predictive of long term survival outcome. To compare arms with respect to vaccine effects on circulating tumor cell (CTC) levels (US sites only). 3.2 Study Endpoints 3.2.1 Primary Efficacy Endpoint The primacy efficacy endpoint for the trial is overall survival. 3.2.2 Secondary Efficacy Endpoint The secondary efficacy endpoint for the study is the proportion of event -free subjects (radiologi cal progression, pain progression, chemotherapy initiation, or death) at six months (or early termination) compared to placebo. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 34 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 4.0 INVESTIGATIONAL PLAN 4.1 Study Design BNIT -PRV- 301 is a randomized, placebo- controlled, multi -center, multi -country, Phase 3 efficacy trial of PROSTVAC -V/F in men with asymptomatic or minimally symptomatic, metastatic, castration- resistant prostate cancer. Subjects will be randomized with equal probability (1:1:1) to one of three double- blind arms; two investigational arms (Arm V+G; Arm V), and a control arm (Arm P). The study will consist of three periods: a Screening phase, followed by Treatment, and subsequently Long- Term Follow -Up (LTFU) phases. The intended intervention in Arm V+G is PROSTVAC -V/F plus GM- CSF; Arm V intended intervention is PROSTVAC -V/F plus GM- CSF placebo, whereas the intended intervention in Arm P is vaccine placebo plus GM- CSF placebo. The trial interventions will consist of a single sc immunization of PROSTVAC -V or placebo in Week 1, followed by six PROSTV AC-F or placebo immunizations administered in Weeks 3, 5, 9, 13, 17, and 21. Each immunization will be accompanied by administration of sc GM- CSF or placebo on the day of immunization and for the subsequent three days (sc injection within 5 mm of the orig inal PROSTVAC V/F or placebo injection site). The Treatment phase of this trial lasts for five months and is followed by an End- of-Treatment visit at Week 25. During the Treatment phase, subjects will continue to be treated with vaccination therapy or placebo through PSA and/or radiological progression. Following the completion of the Treatment phase (after the last dose of PROSTVAC -V/F + GM-CSF or placebo or early termination of treatment ) of the trial, all subjects will automatically enter the LTFU phase with study visits occurring every six months. During LTFU subjects will receive standard- of-care treatment as determined by the Principal Investigator or treating physician. The appropriate timing and the nature of any subsequent treatment will be at the discretion of the Principal Investigator or treating physician. All treatments for mCRPC subsequent to the Treatment phase of the trial will be documented in the CRF. This comprehensive data will be collected until study closure, death, or until a subject withdraws from the study. The primary endpoint for the study is overall survival. All subjects will be followed for 12 months after the required number of 534 events for each between- arm comparison is realized. 4.2 Sample Size This study will evaluate approximately 1,200 subjects (400 subjects/arm) with a 1:1:1 randomization of PROSTVAC -V/F plus or minus GM- CSF versus placebo control plus GM- CSF placebo. 4.3 Selection of Study Population All subjects will be men ≥ 18 years old with asymptomatic or minimally sympt omatic, metastatic CRPC. Subjects will have progressive disease following androgen suppression or complete blockade therapy, or surgical castration; and will be chemotherapy naïve for metastatic prostate cancer. Subjects must be Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 35 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. vaccinia experienced (previous smallpox vaccination). Subjects must have a castrate testosterone level of <50 ng/dl at study entry. For subjects on anti- androgens, a 6- week washout is required (4 weeks if on flutamide). Prospective subjects may be screened from hospital or clinic records or databases, or may be new patients. At the discretion of the institution, subjects may be recruited by advertisements, on- line, in newsletters or journals, flyers, or on radio provided the content and distribution is approved by BNI and by the IRB/EC prior to use or release. BNI will list the study on the government website, www.clinicaltrials.gov. 4.4 Targeted Enrollment of Minorities Attempts will be made (in the US) to specifically enroll minority subjects up to the level of representation in the general US population. Cities with high minority populations will be specifically targeted for center recruitment, as will study centers serving primarily minority populations; e.g., Historically Black Colleges and Universities. Attempts will be made to tailor advertising and recruitment tools to minority groups and to enlist the help of subject advocacy groups in high minority population centers. 4.5 Method of Assigning Subjects to Treatment Groups This study is double- blind and placebo- controlled. Enrollment will be randomized with equal probability to each of three double- blinded arms: two investigational arms (Arm V+G or Arm V) and a control arm (Arm P). The intended interventions associated with the arms are: active treatment with PROSTVAC -V/F + GM-CSF (Arm V+G); PROSTVAC -V/F + GM -CSF placebo (Arm V); or placebo control (Arm P). Block randomization will be used to randomly assign subjects in a 1:1:1 manner. Randomization wil l be stratified according to the following two factors, PSA (equal and above or below 50 ng/ml) and LDH (equal and above or below 200 U/m L). 4.6 Inclusion Criteria Eligible subjects must meet all the following criteria (there will be no exemptions for Inclusi on/Exclusion criteria): 1. Signed Informed Consent.