Key f eatures are summarized below. This study will be monitored by an independent Data Monitoring Committee and the charter for this committee is based on FDA guidance. 9.1 Study Design This 1,200 subject (approximately) study is a randomized, double- blind, placebo- controlled, three- arm clinical trial. The primary endpoint is survival time or time to the most recent knowledge of “known to be alive” (censored time). Zero time is defined as the date of randomization. Subjects will be randomly partitioned with equal probability into one of three double- blinded arms, an investigational arm where the intended intervention is vaccine (PROSTVAC -V/F) plus GM- CSF (Arm V+G), an investigational arm where the intended intervention is vaccine (PROSTVAC -V/F) with placebo GM-CSF (Arm V), and a control arm where the intended intervention is an empty fowlpox vector and placebo GM- CSF (Arm P). (Arm V+G) PROSTVAC -V/F plus GM -CSF (Arm V) PROSTVAC -V/F plus GM -CSF placebo (Arm P) Double placebo (empty fowlpox vector / plus GM- CSF placebo) . The association of intervention to arm will be hidden from clinical personnel and subjects by using a coded identifier for each intervention preparation to be administered. Specifically, the arm designators shown above (V+G, V, and P) are for statistical purposes. 9.2 Randomization Block randomization will be used to randomly assign subjects in a 1:1:1 manner. Randomization will be stratified by PSA (equal and above, or below 50 ng/mL ), and LDH (equal and above, or below 200 u/L). Subjects will be randomized through IVRS/IWRS. 9.3 Analysis Sets Three analysis sets are defined for this trial. The Intent -to-Treat set (ITT) includes all subjects who are randomized. The full analysis set (FAS) includes all subjects initiating study intervention. The safety analysis set includes all subjects initiating study intervention. The FAS and safety analysis set are the same. All efficacy analyses will be performed on the ITT set and the FAS. Subjects will be analyzed and summarized based on the arm into which they were randomized. Efficacy analysis performed on the ITT analysis set will be considered to be the primary indicator of efficacy. Analysis performed on the FAS will be considered to be supportive. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 63 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. All sa fety a nalyses w ill be per formed on the Safet y set. 9.4 Primary Efficacy Analysis Two main overall comparisons of survival time are planned: A comparison between Arm V+G and Arm P, and a comparison between Arm V and Arm P. Thus two separate tests will be assessed, and success for the trial is defined as meeting statistical criterion for either of the following comparisons. • Superiority of Arm V+G over Arm P for all subjects randomized to these arms. • Superiority of Arm V over Arm P for all subjects randomized to these arms. The overall type one error probability (alpha error) for the whole study is designed as a one sided P=0.025. There are two main overall comparisons, which therefore necessitate a type one error probability to 0.0125 for each comparison based on using a Bonferroni correction. The primary analysis methodology will be the stratified log rank test. 9.5 Trial Size The Arm P reference data for planning this trial is specified as a median survival of 22 months based on the placebo arm of Dendreon D9902B. Based on exponential assumptions the corresponding hazard rate is 0.3781 and the corresponding three- year survival is 32.2%. The hazard ratio to be used in the specific alternative hypotheses used to compute trial size is specified to be 0.68 for the main comparisons, that is, a 32% smaller hazard rate in Arm V+G or Arm V as compared to Arm P. This hazard ratio is based on hazard ratio estimates from the previously completed randomized Phase 2 trial with an allowance that the Phase 2 trial likely provides an over -optim istic estimate of the true hazard ratio. The hazard ratio estimate from the Phase 2 trial was 0.56, and was approximately 0.5 when delayed effect is taken into account (depending on the characterization of the delayed effect). Simulations project that 534 events for each between- arm comparison are required for a minimum of 85% power to detect a 32% lower hazard rate. These calculations have taken in to consideration a delayed treatment effect (as found in the randomized phase 2 study). If there is less delayed effect the power will be greater. The projection for the time to realize the required number of deaths for final analysis is 4.6 years following the start of accrual. 9.6 Secondary Efficacy Endpoint The secondary efficacy endpoint is a binary assessment for Alive without Event (AWE) at six months (or early termination). The event is any of the following on or before six months: radiological progression, pain progression, chemotherapy initiation, or death. Subjects without an event prior to six months wil l have an evaluation for event at six months. Subjects without event who are not evaluated at six months (or early termination) will be assumed to have had an event. Thus, each subject will be defined as AWE = Protocol BNIT -PRV - 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 64 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 1 if the subject is alive and free of event at six months (or early termination) and AWE = 0 otherwise. AWE will have a realization for every subject and therefore is amendable to an intent -to-treat analysis. The same two comparisons as done for survival will be done for AWE, using the same significance levels. For each comparison the proportions of subjects in each arm for which AWE = 1 will be compared. The probability is 90% or greater that this statistical test will be significant if the true proportion difference is 0.1375 or greater. The critical difference is 0.092 if the control arm proportion is 0.5. 9.7 Safety Analyses The primary safety analysis set will be all subjects initiating study intervention. The primary focus will be a between - arm comparison of the frequency and severity of safety even ts without attribution. Supporting analyses will be comparisons of subjects according to intervention received and attribution. Adverse events will be summarized and tabulated by severity and by relationship to study intervention (attribution). The original terms used by investigators to identify AEs in the CRFs will be translated into preferred terms using current MedDRA Thesaurus. The AEs will be grouped by MedDRA preferred terms into frequency tables according to body system. The number and percentage of subjects experiencing adverse events will be tabulated by body system/preferred term and treatment. When an AE occurs more than once, the maximum severity and causality will be listed only once. Additionally, SAEs and AEs that are possibly or probably related to study intervention will be summarized separately. Data listings of all AEs will be provided by individual subject. 9.8 Interim Analyses An interim analysis plan (IAP) is included in the SAP for this study. Interim analyses are executed by a Contract Research Organization that acts as the independent statistician and assessed by the DMC as described in the DMC Charter. At each interim analysis, both unblinded (closed) and blinded (open) interim analysis reports will be provided to the DMC, while the sponsor will only receive an open (blinded) report unless one of the criteria is met. Even in this case , the DMC will use its discretion regarding the communications of results to the sponsor, with patient safety balanced ag ainst benefit being the primary concern. The IAP was designed to detect early evidence of both efficacy and futility. Interim analyses for the two comparisons of overall survival described in Section 9.4 are to be executed at 40%, 60%, and 80% of information times, corresponding to 214, 321, and 427 deaths per comparison. The final analysis will be completed when 534 deaths per comparison ha ve occurred. To maintain an overall one - sided type I error probability of 0.0125 per comparison, the one - sided significance criteria using one - sided O’Brien - Flemming boundaries for early detection of efficacy analyses are 0.000135, 0.00147, 0.00501, respe ctively, with the adjusted final analysis to use 0.01063. The significance level to be used for detection of futility at each interim analysis is 0.00001. This futility significance level was chosen in order Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 65 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. to provide a balance between the sought for estimated probability of detecting futility and protecting against falsely detecting futility. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 66 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 10.0 STUDY ADMINISTRATION AND INVESTIGATOR OBL IGATIONS 10.1 Regulatory and Ethical Compliance This clinical study was designed and will be implemented in accordance with the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local regulations (including US Code of Federal Regulations Title 21 and European Directive 2001/20/EC), and with the ethical principles laid down in the D eclaration of Helsinki. 10.2 Institutional Review Board (IRB), Research Ethics Board (REB), and Independent Ethics Committee (IEC) Approval The Investigator will submit this protocol, the informed consent, Investigator Brochure, and any other relevant supporting information (e.g., all advertising materials or materials given to the subject during the study) to the appropriate IRB/REB/IEC for review and approval before study initiation. Amendments to the protocol and informed consent form must also be approved by the IRB/REB/IEC before the implementation of changes in this study. The Investigator is responsible for providing the IRB/REB/IEC with any required information before or during the study, such as SAE expedited reports or study progress reports. The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) (unless a waiver to the IRB requirements of the 1572 has been obtained) as well as country -specific national regulations and/or local laws. The following documents must be provided to BNI or its authorized representative before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal approval; and (2) a copy of the IRB/REB/IEC -approved ICF. 10.3 Institutional Biosafety Committee (IBC) (where appl icable) This protocol and any accompanying material provided to the subject (such as subject information sheets, Informed Consent Form, or descriptions of the study used to obtain informed consent) will be submitted by BNI and/or the site to a legally constituted and chartered Institutional Biosafety Committee (IBC). Additional materials, such as the Investigator’s Brochure, will be submitted to the IBC according to the specific Committee and federal (United States’ National Institutes of Health or foreign equivalent) requirements. Each site will be approved by the IBC in accordance with local procedures and country - specific regulatory requirements. Documentation of IBC approval must be in place prior to drug shipment to the site. At the discretion of the specific IBC and within federal requirements, IBC oversight of individual sites may be terminated provided (1) all subjects at that site have completed dosing by at least 28 days, and (2) all investigational materials have been fully accounted for and either returned to BNI, destroyed on site, or Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 67 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. shipped to a duly licensed destruction facility and a shipping and inventory reconciliation records have been filed in the Pharmacy Manual. 10.4 Informed Consent The informed consent form (ICF) and process must comply with the United States regulations (§ 21 CFR Part 50) as well as country specific national regulations and/or local laws. The ICF will document the study -specific information the Investigator or his/her designee provides to the subject and the subject’s agreement to participate. The Investigator, or designee (designee must be listed on the Delegation of Authority log), must explain in terms understandable to the subject the purpose and nature of the study, study procedures, anticipated benefits, potential risks, possible adverse effects, and any discomfort participation in the study may entail. This process must be documented in the subject’s source record. Each subject must provide a signed and dated informed consent before any study -related (nonstandard of care) activities are performed (such as screening). The original and any amended signed and dated consent forms must remain in each subject’s study file at the study site and be available for verification by study monitors at any time. A copy of each signed consent form must be given to the subject at the time that it is signed by the subject. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 68 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 11.0 CONTROL AND QUALITY ASSURANCE 11.1 Protected Subject Health Information Authorization Information on maintaining subject confidentiality in accordance to individual local and national subject priva cy regulations must be provided to each subject as part of the informed consent process (refer to Section 10.4) either as part of the informed consent form or as a separate signed document (for example, in the US, a site- specific Health Insurance Portability and Accountability Act [HIPAA] consent may be used). The Investigator or designee must explain to each subject that for the evaluation of study results, the subject’s protected health information obtained during the study may be shared with BNI and its designees, regulatory agencies, and IRBs/REBs/IECs. As the study Sponsor, BNI will not use the subject’s protected health information or disclose it to a third party without applicable subject authorization. It is the Investigator’s or designee’s responsibility to obtain written permission to use protected health information from each subject. If a subject wit hdraws permission to use protected health information, it is the Investigator’s responsibility to obtain the withdrawal request in writing from the subject and to ensure that no further data will be collected from the subject. Any data collected on the subject before withdrawal will be used in the analysis of study results. During the review of source documents by the monitors or auditors, the confidentiality of the subject will be respected with strict adherence to professional standards and regulations. 11.2 Study Files and Record Retention The Investigator must keep a record that lists all subjects considered for enrollment (including those who did not undergo screening) in the study. For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be recorded. The Investigator/study staff must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. Essential documentation includes, but is not limited to, the Investigator ’s Brochure, signed protocols and amendments, IRB/REB/IEC approval letters (dated), signed FDA Form 1572 and Financial Disclosures, signed ICFs (including subject confidentiality information), drug dispensing and accountability records, shipping records of investigational product and study -related materials, signed (electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms transmitted to BNI or designee and notification of SAEs and related reports, source documentation, normal laboratory values, decoding procedures for blinded studies, curricula vitae for study staff, and all relevant correspondence and other documents pertaining to the conduct of the study. All essential documentation will be retained by the Investigator for at least 2 years after the date the last marketing application is approved for the drug for the indication for which it is being investigated and until there are no pending or contemplated marketing applications; or, if no application is to be filed or if t he application is not approved for such indication, until 2 years after formal discontinuation of clinical development of the drug. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 69 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. The Investigator must notify BNI and obtain written approval from BNI before destroying any clinical study documents or images (e.g., scan, radiograph, ECG tracing) at any time. Should an Investigator wish to assign the study records to another party or move them to another location, advance written notice will be given to BNI . BNI will inform the Investigator of the date that study records may be destroyed or returned to BNI. BNI must be notified in advance of, and BNI must provide express written approval of, any change in the maintenance of the foregoing documents if the Investigator wishes to move study records to another location or assign responsibility for record retention to another party. If the Investigator cannot guarantee the archiving requirements set forth herein at his or her study site for all such documents, special arrangements must be made between the Inves tigator and BNI to store such documents in sealed containers away from the study site so that they can be returned sealed to the Investigator for audit purposes. 11.3 Case Report Forms and Record Maintenance Electronic case report forms (eCRFs) will be used to collect the clinical study data and must be completed for each enrolled subject with all required study data accurately recorded such that the information matches the data contained in medical records (e.g., physicians’ notes, nurses’ notes, clinic charts and other study -specific source documents). Authorized study site personnel (i.e., listed on the Delegation of Authority form) will complete eCRFs designed for this study according to the completion guidelines that will be provided. The Investigator will ensure that the eCRFs are accurate, complete, legible, and completed within 5 days of each subject’s visit. At all times, the Investigator has final responsibility for the accuracy and authenticity of all clinical data. The eCRFs exists within an electronic data capture (EDC) system with controlled access managed by BNI or its authorized representative for this study. Study staff will be appropriately trained in the use of eCRFs and application of electronic signatures before the start of the study and before being given access to the EDC system. Original data and any changes of data will be recorded using the EDC system, with all changes tracked by the system and recorded in an electronic audit trail. The Investigator attests that the information contained in the eCRFs is true by providing electronic signature within the EDC system. After database lock, the Investigator will receive a copy of the subject data (e.g., paper, CD-ROM or other appropriate media) for archiving at the study site. 11.4 Study Monitoring/ Audit Requirements Representatives of BNI or its designee will monitor this study until completion. Monitoring will be conducted through personal visits with the Investigator and site staff, remote monitoring, as well as any appropriate communications by mail, fax, email, or telephone. The purpose of monitoring is to ensure that the study is conducted in compliance with the protocol, standard operating procedures (SOPs), and other written instructions and regulatory guidelines, and to ensure the quality and integrity of the data. This study is also subject to reviews or audits. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 70 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor have access to all original source documents, including all electronic medical records (EMR) at reasonable times and upon reasonable notice. During the review of source documents, every effort will be made to maintain the anonymity and confidentiality of all subjects during this clinical study. However, because of the experimental nature of this treatment, the Investigator agrees to allow the IRB/REB/IEC, representatives of BNI , its designated agents and authorized employees of the appropriate Regulatory Authority to inspect the facilities used in this study and, for purposes of verification, allow direct access to the hospital or clinic records of all subjects enrolled into this study. A statement to this effect will be included in the informed consent and permission form authorizing the use of protected health informat ion. BNI or its authorized representative may perform an audit at any time during or after completion of this study. All study -related documentation must be made available to the designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may choose to inspect a study site at any time before, during, or after completion of the clinical study. In the event of such an inspection, BNI will be available to assist in the preparation. All pertinent study data should be made available as requested to the Regulatory Authority for verification, audit, or inspection purposes. 11.5 Investigator Responsibilities A complete list of Investigator responsibilities are outlined in the clinical trial research agreement and the Statement of Investigator FDA Form 1572, both of which are signed by the Investigator before commencement of the study. In summary, the Investigator will conduct the study according to the current protocol; will read and understand the Investigator’s Brochure; will obtain IRB/REB/IEC approval to conduct the study; will obtain informed consent from each study participant; will maintain and supply to the Sponsor or designee, auditors and regulatory agencies adequate and accurate records of study activity and drug accountability for study -related monitoring, audits, IRB/REB/IEC reviews and regulatory inspections; will report SAEs to the Sponsor or designee and IRB/ REB/IEC according to the specifics outlined in this protocol; will personally conduct or supervise the study; and will ensure that colleagues participating in the study are informed about their obligations in meeting the above commitments. 11.6 Sponsor Responsibilities A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement and in the laws and regulation of the country in which the research is conducted. In summary, the Sponsor will select qualified Investigators, provide them with the information they need to properly conduct the study, ensure adequate monitoring of the study, conduct the study in accordance with the general investigational plan and protocols and promptly inform Investigators, health and regulatory agencies/authorities as appropriate of significant new adverse effects or risks with respect to the drug. 11.7 Financial Disclosure A separate financial agreement will be made between each Principal Investigator and BNI or its authorized representative before the study drug is delivered. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 71 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. For this study, each Investigator and Sub- investigator (as designated on the FDA 1572 form) will provide a signed Financial Disclosure Form in accordance with § 21 CFR 54. Each Investigator will notify BNI or its authorized representative of any relevant changes during the conduct of the study and for 1 year after the study has been completed. 11.8 Liability and Clinical Trial Insurance In the event of a side effect or injury, appropriate medical care as determined by the Investigator/designee will be provided. If a bodily injury is sustained, resulting directly from the use of the study drug, BNI will reimburse for reasonable physician fees and medical expenses necessary for treatment of only the bodily injury which is not covered by the subject’s medical or hospital insurance, provided that the injury is not due to a negligent or wrongful act or omission by the Investigator/study staff. The Informed Consent Form will include a description of this reimbursement policy, incorporating country -specific national regulations and/or local laws. Financial compensation for lost wages, disability or discomfort due to the study is not available. Clinical trial insurance has been undertaken according to the laws of the countries where the study will be conducted. An insurance certificate will be made available to the participating sites at the time of study initiation upon request. 11.9 Protocol Amendments BNI will initiate any change to the protocol in a protocol amendment document. The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised model informed consent form (ICF). Written documentation of IRB/REB/IEC and required site approval must be received by BNI before the amendment may take effect at each site. Additionally under this circumstance, information on the increased risk and/or change in scope must be provided to subjects already actively participating in the study, and they must read, understand and sign any revised ICF confirming willingness to remain in the trial. No other significant or consistent change in the study procedures, except to eliminate an immediate hazard, shall be effected without the mutual agreement of the Investigator and BNI. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 72 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 12.0 PUBLICATION OF STUDY RESULTS BNI may use the results of this clinical study in registration documents for Regulatory Authorities in the United States or abroad. The results may also be used for papers, abstracts, posters or other material presented at scientific meetings or published in professional journals or as part of an academic thesis by an Investigator. In all cases, to avoid disclosures that could jeopardize proprietary rights and to ensure accuracy of the data, BNI reserves the right to preview all manuscripts and abstracts related to this study, allowing BNI sufficient time to make appropriate comments before submission for publication. In most cases, the Principal Investigators at the sites with the highest accruals of eligible subjects shall be listed as lead authors on manuscripts and reports of study results. This custom can be adjusted upon mutual agreement of the authors and BNI . 12.1 Study Discontinuation The Sponsor reserves the right to terminate the study at any time. Should this be necessary, both the Sponsor and the Investigator will arrange discontinuation procedures. In terminating the study, the Sponsor and the Investigator will assure that adequate consideration is given to the protection of the subjects’ interests. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 73 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 13.0 REFERENCES 1.