End of study procedures: Data will be stored according to HHS, FDA regulations and NIH Intramural Records Retenti on Schedule as applicable. Loss or destruction of data: Should we become aware that a majo r breach in our plan to protect subject confidentiality and trial data has occurred, the IRB will be notified. 6.2 R ESPONSE CRITERIA Patients will not undergo scheduled radiographic assessment for metastatic disease unless clinically indicated for increasing PSA or symptoms. 6.2.1 Disease Progression 6.2.1.1 PSA will not be used to measure progressi on of disease given the intermittent use of enzalutamide. It is expected that PSA will rise after a 3 month course of enzalutamide is completed and the treatment is discontinued. Patients will be offered androgen deprivation therapy (ADT) as clinically indicated or a second course of enzalutamide as indicated in the protocol. Starting ADT will be done at the discretion of the investigator, although this will result in treatment termination and removal from the clinical trial. (Conventionally this is when PSA has a doubling time of less than 3 months, but patients may refuse treatment in favor of surveillance which is also clinically appropriate. Conversely, patie nts may go on ADT at any time, although this Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 42may result in removal from the trial.) PSA w ill be used to calculate PSA kinetics/tumor growth kinetics. 6.2.1.2 Development of a new bone lesion. 6.2.1.3 Development of a soft tissue mass, identifie d on CT scan or physical exam, consistent with metastatic prostate cancer. If identified on physical exam, the lesion may be biopsied to confirm the presence of prostate cancer. 6.2.1.4 Development of urethral, ureteral, or sp inal cord obstruction secondary to tumor. 6.2.1.5 Development of cytologically positive pleural effusion or lymphangitic spread in the lungs. 6.2.1.6 Symptoms which in the opinion of the investigator are consistent with clinical progression. 6.3 T OXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 ). 7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 7.1 D EFINITIONS 7.1.1 Adverse Event Any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in re search, whether or not considered related to the subject’s participation in the research.7.1.2 Suspected adverse reactionSuspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. 7.1.3 Unexpected adverse reactionAn adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the sp ecificity or severity that has been observed; or, if an investigator brochure is not required or available, is not cons istent with the risk information described in the general inve stigational plan or elsewhere in the current application. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 43"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug und er investigation. 7.1.4 Serious An Unanticipated Problem or Prot ocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety , welfare or rights of subjects or others. 7.1.5 Serious Adverse EventAn adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following: xDeath, xA life-threatening adverse drug experience xInpatient hospitalization or prolongation of existing hospitalization xPersistent or significant incapacity or s ubstantial disruption of the ability to conduct normal life functions xA congenital anomaly/birth defect. xImportant medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 7.1.6 Disability A substantial disruption of a person’s ability to conduct normal life functions. 7.1.7 Life-threatening adverse drug experience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 7.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure fro m the IRB-approved research protocol. 7.1.9 Non-compliance (NIH Definition)The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects. 7.1.10 Unanticipated ProblemAny incident, experience, or outcome that: xIs unexpected in terms of nature, se verity, or frequency in relation to Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 44(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator’s Brochure or other study documents, and (b) the characteristics of the subject population being studied; AND xIs related or possibly related to participation in the research; AND xSuggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. 7.2 NCI-IRB AND CLINICAL DIRECTOR REPORTING 7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: xAll deaths, except deaths due to progressive disease xAll Protocol Deviations xAll Unanticipated Problems xAll non-compliance Reports must be received within 7 days of PI awareness via iRIS. 7.2.2 NCI-IRB Requirements for PI Reporting at Continuing ReviewThe protocol PI will report to the NCI-IRB: 1. A summary of all protocol deviations in a ta bular format to include the date the deviation occurred, a brief description of the deviation and any corrective action. 2. A summary of any instances of non-compliance 3. A tabular summary of the following adverse events: xAll Grade 2 unexpected events that are possibly, probably or definitely related to the research; xAll Grade 3 and 4 events that are possibly, probably or definitely related to the research; xAll Grade 5 events regardless of attribution; xAll Serious Events regardless of attribution. NOTE : Grade 1 events are not required to be reported. 7.2.3 NCI-IRB Reporting of IND Safety Reports Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NCI IRB. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 457.3 IND S PONSOR REPORTING CRITERIA During the first 30 days after the subject re ceives investigational agent/intervention, the investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a, any serious adverse event, whether or not c onsidered drug related, including those listed in the protocol or investigator brochure and must include an a ssessment of whether there is a reasonable possibility that the drug caused the event. For serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention, only report those that have an attribution of at least possibly related to the agent/intervention. Required timing for reporting per the above guideline: xDeaths (except death due to progressive dis ease) must be reported via email within 24 hours. A complete report must be submitted within one business day. xOther serious adverse events as well as de aths due to progressive disease must be reported within one business day Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov, and to the CCR PI and study coordinator. 7.3.1 Reporting Pregnancy 7.3.1.1 Paternal exposureMale patients should refrain from fathering a ch ild or donating sperm during the study and for 3 months after the last dose of study treatment. Pregnancy of the patie nt’s partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, nor mal birth, or congenital abnorma lity) occurring from the date of the first dose until 3 months after the last dose should, if possible, be followed up and documented. 7.4 S AFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov . The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. 7.4.1 Reporting to Astellas The Investigator should complete and submit an SAE Medwatch 3500 Form, containing all information that is required by the Regulatory Authorities, to Astellas by either e-mail or fax within 24 hours of awareness whether or not relate d to the study drug. If submission of this SAE by email or fax or is not possible within 24 hours, the local drug safety contact (IRB, Investigator, etc.) should be informed by phone. The SAE documentation, including the Medwat ch 3500 Form and available source records, should be emailed or faxed to: Astellas Pharma Global Development – United States Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 46Email: Safety-us@us.astellas.com Fax number: (847) 317-1241 The following minimum information is required: xStudy number/IIT regulatory identifier xSubject number, sex and age xThe date of report xA description of the SAE (eve nt, seriousness of the event) xCausal relationship to the study drug Follow-up information for the event should be sent within 7 days as necessary. 7.4.2 Reporting to Bavarian Nordic, Inc. The investigator should also submit all safety reports that are sent to the FDA using the Medwatch 3500 Form to: Bavarian Nordic, Inc. Email: pharmacovigilance@bavarian-nordic.com ; Fax number for pharmacovigilance at BN: 888-465-1219 Attention: Karen Latina 7.5 I NSTITUTIONAL BIOSAFETY COMMITTEE (IBC) R EPORTING CRITERIA 7.5.1 Serious Adverse Event Reports to OSP/IBC The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life- threatening experience associated with the us e of PSA-TRICOM Vaccine as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpected and associated with the use of the PSA-TRICOM Vaccine, but are not fatal or life-threatening, much be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator’s initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a. 7.5.2 Annual Reports to IBCWithin 60 days after the one-year anniversary of the date on which the IBC approved the initial protocol, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to the IBC in lieu of a separate repor t. Please include the IBC protocol number on the report. 7.5.2.1 Clinical Trial Information A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information: Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 47xthe title and purpose of the trial xclinical site xthe Principal Investigator xclinical protocol identifiers; xparticipant population (such as disease indication and general age group, e.g., adult or pediatric); xthe total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a bri ef description of the reasons xthe status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, xif the trial has been completed, a brief description of any study results. 7.5.2.2 Progress Report and Data Analysis Information obtained during the previous year's clinical and non-clin ical investigations, including: xa narrative or tabular summary showing th e most frequent and most serious adverse experiences by body system xa summary of all serious adverse events submitted during the past year xa summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transf er product such as disease progression or concurrent medications xif any deaths have occurred, the number of pa rticipants who died during participation in the investigation and causes of death xa brief description of any information obtained that is pertinent to an understanding of the gene transfer product’s actions, including, fo r example, informati on about dose-response, information from controlled trials, a nd information about bioavailability. 7.6 D ATA AND SAFETY MONITORING PLAN 7.6.1 Principal Investigator/Research Team The Principal Investigator, lead associate investigator and the research nurse will meet weekly at each clinic to review all adverse events for each subject in this trial and to determine dose limiting toxicities and escalation rules. Unexpected adverse events and/or serious adverse events will be reported to the NCI’s Institutional Review Board (IRB ) and sponsor/FDA as outlined above. If trends are noted and/or risks warr ant it, accrual will be in terrupted, dose levels expanded and/or the protocol and/or consent will be modified accordingly. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Adverse events will be reported as required above. Any safety concerns, Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 48new information that might affect either the ethical and or scie ntific conduct of the trial, or protocol deviations w ill be immediately reported to the IRB using iRIS and to the Sponsor. The principal investigator will review adverse ev ent and response data on each patient to ensure safety and data accuracy. The principal invest igator will personally conduct or supervise the investigation and provide appr opriate delegation of responsib ilities to other members of the research staff. 7.6.2 Sponsor Monitoring Plan As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR’s program allows for confirmation of: study data, specifically data that could affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on: xInformed consent process xEligibility confirmation xDrug administration and accountability xAdverse events monitoring xResponse assessment. The monitoring program also extends to multi-site research when the CCR is the coordinating center.This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified by training and experience to monitor the progres s of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct. Safety Monitoring Committee (SMC) This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NCI-IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if th ere is no accrual within the review period. Written outcome letters will be generated in response to the monito ring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 8 STATISTICAL CONSIDERATIONS 8.1.1 Cohort 1The primary objective of this study is to compare th e change in the growth rate in the two arms from the time of discontinuation of enzalutamide (3 months after enrollment) to 4 months after completing enzalutamide therapy +/- PSA-TRICOM (7 months after enrollment). With growth rate changes obtained on all patie nts on both arms, and if the grow th rate changes in the two arms had the same standard de viation, with 17 patients per arm, there would be 80% power to detect a difference between the arms equal to 1 SD of the difference from baseline to 7 months with a two-tailed 0.05 signifi cance level two-group t-test .Thus, a total of 34 evaluable patients Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 49are required for analysis. To allow for a sma ll number of patients w ho do not develop a 25% decline in PSA after 3 months, additional patients will be randomized if necessary to obtain a minimum of 17 evaluable patients on each arm. In order to allow for a small number of such patients, the accrual ceiling will be 38. Patients will be stratif ied based a doubling time of greater than or less than 6 months. Secondary endpoints will be compared between th e two arms using appr opriate non-parametric tests, such as a Wilcoxon rank sum test. Results will be presented without formal adjustment for multiple comparisons but reported in the context of secondary evaluation of a potentially large number of endpoints. The significance of paired hormone level results within arms will be determined by a paired t-test or W ilcoxon signed rank test as appropriate. 8.1.2 Halting Rules The study will be halted for review of changes to the protocol and consent if either of the following is met: xOne occurrence of grade 5 toxicity attributed to the treatment regimen. xTwo occurrences of grade 4 toxicity attributed to the treatment regimen. 8.1.3 The regression-growth equation The equation is f(t) = exp(-d * t)+exp(g * t) - 1 (A) where exp is the base of the natural logarithm, e= 2.7182, and f(t) is the tumor (or in MTC calcitonin) measurement at time tin days, normalized to (divided by) the tumor measurement at day 0, the time at which treatment is commenced. Rate constant d(decay, in daysí) represents the exponential decrease/regression of the a serum tumor marker (i.e. PSA) signal during therapy. Rate constant g(growth, also in daysí) represents the exponential growth/regrowth of the tumor during treatment. These rate constants may be expressed in terms of half-lives and doubling times. Thus, dequals ln 2(0.693) divided by the time it takes for the regressing part to shrink by half, whereas gequals ln 2divided by the time for the growing component to double. ( 44) Two earlier papers depict theoretical curves de picting the separate components of Equation (A) and how these combine together to give the time dependence of the tumor size, f.(44)When the data showed a continuous decrease from the time of treatment start, so that only the regression parameter dwas found to differ significantly from zero with P< 0.05, Equation (A) was replaced by the following reduced form, with the growth rate constant eliminated: f(t) = exp(-d * t )( B ) When tumor measurements showed a continuous increase, so that only the growth parameter g was found to differ significantly from zero with P< 0.05, Equation (A) was replaced by the following reduced form, with the decay constant eliminated: f(t) = exp(g *t) . 8.1.4 Data Analysis For each patient an attempt to fit Equation (A) to each data set for which more than one data point is available. Curve fittingbo will be performed using Sigmaplot (Systat Software), or by Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 50using the Solver routine in an Excel spreadsheet. We will extract parameters g and d with their associated Student's t and P values.