60 8.14 Serious Adverse Events ........................................................................... 60 8.15 Treatment and Follow -up of Adverse Events or Serious Adverse Events ...................................................................................................... 61 9.0 STATISTICAL CONSIDER ATIONS ................................................................... 62 9.1 Study Design ........................................................................................... 62 9.2 Randomization ......................................................................................... 62 9.3 Analysis Sets ........................................................................................... 62 9.4 Primary Efficacy Analysis ......................................................................... 63 9.5 Trial Size .................................................................................................. 63 9.6 Secondary Efficacy Endpoint ................................................................... 63 9.7 Safety Analyses ....................................................................................... 64 9.8 Interim Analyses ...................................................................................... 64 10.0 STUDY ADMINISTRATION AND INVESTIGATOR OBL IGATIONS ................. 66 10.1 Regulatory and Ethical Compliance ......................................................... 66 10.2 Institutional Review Board (IRB), Research Ethics Board (REB), and Independent Ethics Committee (IEC) Approval ....................................... 66 10.3 Institutional Biosafety Committee (IBC) (where applicable) ..................... 66 10.4 Informed Consent .................................................................................... 67 11.0 CONTROL AND QUALITY ASSURANCE ......................................................... 68 11.1 Protected Subject Health Information Authorization ................................ 68 11.2 Study Files and Record Retention ........................................................... 68 11.3 Case Report Forms and Record Maintenance ......................................... 69 11.4 Study Monitoring/ Audit Requirements ..................................................... 69 11.5 Investigator Responsibilities .................................................................... 70 11.6 Sponsor Responsibilities .......................................................................... 70 11.7 Financial Disclosure ................................................................................. 70 11.8 Liability and Clinical Trial Insurance ......................................................... 71 11.9 Protocol Amendments .............................................................................. 71 12.0 PUBLICATION OF STUDY RESULTS .............................................................. 72 12.1 Study Discontinuation .............................................................................. 72 13.0 REFERENCES ................................................................................................... 73 14.0 APPENDICES .................................................................................................... 80 14.1 Schedule of Events .................................................................................. 80 14.2 NIH RAC Appendix B (excerpt) ................................................................ 82 Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 6 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 14.3 Criteria of Progression for Trial Eligibility by PCWG2 (2007) ................... 83 14.4 ECOG Performance Status Criteria ......................................................... 84 14.5 NYHA Classification – The Stages of Heart Failure ................................. 85 14.6 NCI Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.0)........................................................................................................... 86 14.7 FACT -P Quality of Life Questionnaire ...................................................... 87 14.8 BPI-SF Quality of Life Questionnaire ....................................................... 90 14.9 EQ-5D-3L Quality of Life Questionnaire ................................................... 92 14.10 Vial and Carton Labels ............................................................................. 94 14.11 List of Research Centers ......................................................................... 97 14.12 Rationale and Changes ........................................................................... 97 LIST OF TABLES Table 9-1 Adverse Event Grading Criteria ..................................................................56 Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 7 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. LIST OF ABBREVIATION S AND DEFINITION OF TERMS AE(s) Adverse Event (s) ALT (SGPT) Alanine aminotransferase APC Antigen presenting cell AST (SGOT) Aspartate aminotransferase AWE Alive Without Event BN Bavarian Nordic A/S (Kvistgaard, Denmark) BN-B Bavarian Nordic, Berlin BNI Bavarian Nordic, Inc, formerly known as BNIT BNIT BN ImmunoTherapeutics, Inc. BP Blood pressure BPI-SF Brief Pain Inventory – Short Form BSL Biological Safety Level BUN Blood urea nitrogen CFR Code of Federal Regulations CRF Case report form CT Computerized tomography CTC Circulating tumor cell CTCAE Common Toxicity Criteria for Adverse Events CTL Cytotoxic T -lymphocyte DLT Dose- limiting toxicity DMC Data Monitoring Committee ECOG Eastern Cooperative Oncology Group ECG Electrocardiogram EM Erythema multiforme ePIP electronic Protocol Inquiry Platform EV Eczema vaccinatum FACT -P Functional Assessment of Cancer Therapy - Prostate FAS Full analysis set FDA Food and Drug Administration GCP Good Clinical Practice GM-CSF Granulocyte macrophage- colony stimulating factor HIV Human immunodeficiency virus HLA Human leukocyte antigen HR Hazard ratio IAP Interim Analysis Plan Protocol BNIT -PRV - 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 8 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. IBC Institutional Biosafety Committee ICAM -1 Intercellular adhesion molecule -1 ICH International Conference on Harmonization IDT IDT Biologika, GmbH IND Investigational new drug Inf.U Infectious units IRB/EC Institutional Review Board/ Ethics Committee IU IVRS IWRS International unit Interactive voice response system Interactive web response system LDH Lactate dehydrogenase LFA-3 Leukocyte function associated antigen -3 LLN Lower limit of normal LTFU Long - Term Follow -Up mCRPC metastatic Castration - Resistant Prostate Cancer MHC Major histocompatibility complex MRI Magnetic Resonance Imaging NCI National Cancer Institute NCI-CTCAE National Cancer Institute - Common Toxicity Criteria for Adverse Events NYHA New York Heart Association PAP Prostatic acid phosphatase PBMCs Peripheral blood mononuclear cells PCWG2 Prostate Cancer Clinical Trials Working Group 2 PEI Paul-Ehrlich-Institut PFS Progression - free survival PI Principal Investigator PVG Pharmacovigilance Group PROSTVAC PROSTVAC™, PROSTVAC -V/F, PROSTVAC™ -V/F + TRICOM™ PS Performance status PSA Prostate - specific antigen PV Progressive vaccinia PVE Post-vaccinial encephalitis QoL Quality of Life RAC Recombinant DNA Advisory Committee RR Respiration rate SADR Serious Adverse Drug Reaction SAE Serious adverse event Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 9 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. sc Subcutaneous SUSAR Suspected Unexpected Serious Adverse Reaction TAA Tumor -associated antigen TRICOM TRICOM™, Triad of costimulatory molecules TTP Time to tumor progression ULN Upper limit of normal VIG Vaccinia immune globulin VS Vital signs Protocol BNIT -PRV-301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 10 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. Protocol Synopsis Protocol Title A Randomized, Double -blind, Phase 3, Efficacy Trial of PROSTVAC -V/F ± GM -CSF in Men With Asympto matic or Minimally Symptomatic Metastatic, Castrate -Resistant Prostate Cancer Protocol Number BNIT -PRV-301 IND No. / OBA Protocol Number NCT Number: EudraCT N o. BB-IND 13946 / # 1104 -1101 NCT01322490 2010 -021196 -85 Investigational Product PROSTVAC -V/F Sponsor Bavarian Nordic , Inc. Indication For the treatment of subjects with asymptomatic or minimally symptomatic, metastatic castration -resistant prostate cancer CRO Planned Sample Size 1,200 subjects (approximately) Planned Number of Centers 250 – 300 centers worldwide Study Type Pivotal Study Phase Phase 3 Medical Monitor Drug Safety Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 11 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. PROTOCOL SYNOPSIS Background and Rationale PROSTVAC™ (PROSTVAC -V and PROSTVAC -F; PROSTVAC -V/F) is a novel candidate prostate cancer immunotherapy for the treatment of prostate cancer. It is a viral vector based product that is administered in seven subcutaneous (sc) vaccinations, over a five month period. In a randomized controlled Phase 2 trial, PROST VAC therapy was associated with a prolongation of survival in men with metastatic castration- resistant prostate cancer (mCRPC) . PROSTVAC is a PSA (prostate -specific antigen) -based immunization strategy. It is intended to generate immune responses to prost ate specific antigens and prostate cancer cells. It uses poxviral vectors to introduce modified prostate- specific antigen (PSA) to the patient in an immunogenic manner to break self -tolerance, and thereby induce immune responses directed against prostate cancer cells. PROSTVAC is comprised of two component viral vectors; a recombinant vaccinia (PROSTVAC -V) and a recombinant fowlpox (PROSTVAC -F) virus to be used sequentially in a heterologous prime- boost vaccination regimen. Both viruses contain four human genes: prostate- specific antigen (PSA) and three genes encoding human immunological costimulatory molecules: B7.1, intercellular adhesion molecule- 1 (ICAM- 1), and leukocyte function- associated antigen- 3 (LFA - 3) (designated TRIad of COstimulatory Molecules or TRICOM). The simultaneous expression of PSA and TRICOM enhances the immune response. The PSA transgene is modified at one amino acid (I155L), to enhance binding and immunogenicity of a particular peptide epitope in human leukocyte antigen ( HLA- A2)-expressing patients. PROSTVAC -V/F is the outcome of more than 15 years of poxviral vector development and evaluation by the National Cancer Institute ( NCI), the former Therion Biologics Corporation, and Bavarian Nordic , Inc. Over 570 patients have been t reated with related PSA -containing poxviral vectors, and over 300 patients have been treated with the current PROSTVAC -V/F product. A large database exists from safety evaluations in animals and humans for PROSTVAC -V/F. (see Investigator’s Brochure) Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 12 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 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. It is a 3- arm study and will evaluate overall survival in two separate comparisons, PROSTVAC -V/F plus GM- CSF versus control, and PROSTVAC -V/F without GM- CSF versus control. Subjects will be randomized with equal probability into one of three double- blind arms. The intended interventions for randomized subjects are: (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 trial interventions will consist of a single subcutaneous (sc) immuniz ation of PROSTVAC -V or placebo in Week 1, followed by 6 PROSTVAC -F or placebo sc immunizations administered in Weeks 3, 5, 9, 13, 17, and 21. Each immunization will be accompanied by administration of low dose GM- CSF or placebo on the day of immunization and for the subsequent 3 days (sc injection at same site, within 5 mm). Study Objectives Primary Efficacy Objectives: To ascertain whether the overall 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). Secondary Efficacy Objective : To ascertain whether a greater proportion of subjects randomized to Arm V+G or Arm V remain event -free (radiological progression, pain progression, chemotherapy initiation, or death) at 6 months (or early termination) as compared to the subjects randomized to Arm P. Safety Objectives: To further characterize the safety and tolerability of PROSTVAC immunotherapy. Exploratory Objectives: To model radiological disease status over the first year of study participation. To ascertain whether a greater proportion of subjects randomized to either Arm V+G or Arm V remain event -free (radiological progression) 6 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 analysis will include all subjects, and 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 overall 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 compare arms with respect to immune response to immunizing antigen (PSA), as well as to non- vaccine -contained prostate antigens, and tumor -associated antigens, and assess whether immune responses are prognostic and/or predictive. Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 13 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. 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). Study Type Pivotal Methodology • Subcutaneous immunizations o PROSTVAC -V or placebo administered in Week 1 o PROSTVAC -F or placebo administered in Weeks 3, 5, 9, 13, 17, and 21. Trial Population Subjects with asymptomatic or minimally symptomatic, metastatic prostate cancer who have progressed despite surgical castration or androgen suppression therapy. Subjects will have evidence of radiological disease progression, or PSA disease progression as described in Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, after being treated with androgen suppression therapy or complete androgen blockade and withdrawal. Sample Size It is projected that approximately 1,200 subjects (400 subjects per arm), will be required for evaluation of the primary objective (overall survival). Analysis will require 534 events per each overall efficacy comparison. Arm V+G subjects versus all Arm P subjects, and separately all Arm V subjects versus all Arm P subjects. Duration of Study This trial entails the following three phases: Screening, Treatment, and Long -Term Follow -Up. Screening Phase: Week -4 – 0 Screening procedures have to be completed no more than 4 weeks prior to first planned dose. Treatment Phase: Weeks 1 – 25 Treatment (5 mos), including vaccination at Weeks 1, 3, 5, 9, 13, 17, and 21 followed by End-of-Treatment (Week 25)/Early Termination visit. Due to the delayed effect of vaccine induced immunotherapy, PSA and radiological progression may be expected during the treatment phase of the trial, and is not a cause for stopping vaccination. Subjects who progress clinically (pain) during treatment, or who progress rapidly as measured by PSA- DT <1 month will be counseled with respect to alternative treatment options. If subjects choose to initiate alternative therapy, vaccination will be discontinued. Subjects who stop treatment will continue in the Long- Term Follow -Up ph ase. Long- Term Follow -Up Phase (LTFU): After completing the End- of-Treatment /Early Termination visit, all subjects will automatically enter the Long- Term Follow -Up phase that extends until 12 months after the required number of 534 events for each between- arm comparison is realized. Subject health status, disease status, and subsequent prostate can cer therapies will be collected at each 6 month visit. Summary of Eligibility Criteria . Men ≥ 18 years of age with documented asymptomatic or minimally symptomatic metastatic castration- resistant prostate cancer . Castrate level of testosterone: <50 ng/dl Protocol BNIT -PRV- 301; Amendment 7 PROSTVAC -V/F Version 2.7, 08 February 2017 CONFIDENTIAL AND RESTRICTED 14 Amend 7 Disclosure requires written consent from Bavarian Nordic , Inc. . PSA (or radiological) progression during androgen- suppression or blockade therapy and withdrawal . ECOG PS of 0, or 1 . Life expectancy ≥1 year . Chemotherapy naïve . Subjects requiring scheduled opioid narcotics for cancer -related pain are excluded . Subjects with rapidly progressing disease (estimated PSA -DT <1 month), visceral metastases, or with elevated LDH or elevated alkaline phosphatase (≥2xULN) are excluded . Adequate bone marrow, hepatic, and renal function .