( 44) Data will be analyzed in Excel (Microsoft) and in Sigmaplot 9.0. Linear regressions to evaluate the relationship between the growth rate constant, g, or other parameters will be implemented using the polynomial linear routine of Sigmaplot 9.0. Sample comparisons were performed by Student's t-test, using SigmaStat 3.5 (Systat Software), with Pset at 0.05 for significance. ( 44) 9 COLLABORATIVE AGREEMENTS 9.1 A GREEMENT TYPE 9.1.1 Cooperative Research and Development Agreement (CRADA) xA CRADA (#02859) is in place with Me divation and Aste llas to provide enzalutamide. xA CRADA (#02377) is in place with Bava rian Nordic to provide PSA-TRICOM. 9.1.2 Material Transfer Agreement (MTA) xA MTA is in place with The Cleveland Clin ic Foundation for the studies discussed in section 4.1.6 (MTA#4122006). Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 5110 HUMAN SUBJECT PROTECTIONS 10.1 RATIONALE FOR SUBJECT SELECTION 10.1.1 Selection Based on Gender, Ethnicity, and Race Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. To date, there is no information that suggests th at differences in drug metabolism or disease response would be expected in one group compared with another. Efforts will be made to extend accrual to a representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on one hand and the need to explore ethnic aspects of clinical research on the other hand. If differences in outcome that correlate with ethnic identity are noted, accrual may be expanded or a follow- up study may be written to investigate those differences more fully. Women are not eligible for this study as this diease occurs only in men. 10.1.2 Strategies/Procedures for RecruitmentPatient accrual for this protocol will be facilitated by Web-based recruitment strategies. This protocol will be listed on www.clinicaltrials.gov . 10.1.3 Justification for ExclusionsDue to impaired cellular immunity with the concomitant increased risk of serious side effects from vaccinations with infectious agents, the Centers for Disease Control and Prevention recommends that HIV infected patients be excluded, in addition, patients with chronic hepatitis infection, including B and C, because of potential immune impairment. 10.2 P ARTICIPATION OF CHILDREN Men under the age of 18 will not be eligible for par ticipation in this study based on the fact that patients under 18 are unlikely to have this diseas e and there are unknown toxicities in pediatric patients.10.3 P ARTICIPATION OF NIH S UBJECTS UNABLE TO GIVE CONSENT Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section 7.5), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the “NIH Advance Directive for Health Care and Medical Research Participation” form so that another person can make decisions about their medical care in th e event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a su rrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 5210.4 E VALUATION OF BENEFITS /RISKS/DISCOMFORTS There is no standard therapy for patients with prostate cancer and rising PSA following local definitive therapy. Potential risks of vaccine a nd enzalutamide therapy in this patient population include the range of side effects outlined in section 9. Both drugs have been well tolerated in previous large trials and there are no anticipated overlapping toxicities for patients getting both drugs. 10.4.1 Alternative Approaches or Treatments Patients will be advised verbally and in writing regarding the risks and benefits of this trial, treatment requirements, and alternative approaches to entering the trial. Written consents will be obtained. 10.4.2 Procedures to Eliminate or Minimize Potential Risks This study may involve unforeseeable risks for pati ents, such as side eff ects whose exact nature and severity are unpredictable. Scrupulous care wi ll be taken to minimize such side effects. All patients will be given blood tests, physical examinations, and scans, as described in the monitoring schedule ( Appendix C ), and must have a local physician to provide long-term care and monitoring for complications. Immediate medical treatment is available at the Clinical Center, NCI, Bethesda, Maryland, for any patient s who suffer physical injury as a result of participation in this study. No compensation is available, but any injury will be evaluated and treated in keeping with the benefits or car e to which patients are entitled under applicable regulations. 10.4.3 Provisions for Monitoring Data Collection to Ensure Subject Safety As information is gathered from this trial, clinical results will be shared with patients. Laboratory and clinical data w ill be frequently gathered and an y new significant finding(s) found during the course of the research, which may affect a patient’s willingness to participate further, will be explained. Confidentiality of information concerning participants will be maintained, including in all publications and presentations resulting from this study. Names of participants or material identifying participants will not be released without permission, except as such release is required by law. Records at the National Cancer Institute are maintained according to current legal requirements, and are ma de available for review, as required by the Food and Drug Administration or other authorized users, only und er the guidelines established by the Federal Privacy Act. 10.5 R ISKS/BENEFITS ANALYSIS This study involves clinical research with an experimental vaccine designed to generate an immune response against antigens found in pros tate cancer. Patients will undergo multiple vaccinations. Side effects of the vaccin e are outlined elsewhere (see section 11). Whether the vaccine will have any clinical effect is unknown; therefore, benefit cannot be promised, nor the chance of benefit accurately predicted. Enzalu tamide is an FDA-approved therapy with a known and minimal toxicity profile (section 11). Participation in this study is voluntary, and refusal will not result in penalty or loss of benefit to which the patient is otherwise entitled. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 53The standard of care for patients with nm CSPC includes ADT and active surveillance. Generally, these patients can be followed without therapy until their PSA doubling time escalates at which time ADT is often starte d. All patients in the proposed tr ial will receive enzalutamide. Based on previous trials with high dose bical utamide, 34 of 36 evaluable patients had PSA declines by a median of 96.5% and these nadi rs were achieved within the first 4 weeks of treatment ( 10). We would expect similar if not better results with enzalutamide. Therefore, a clinical trial in this population is ethical and appropriate. The NC I has conducted several trials in this population previously. Participation may be discontinued at any time without penalty, a nd the patient will be encouraged to discuss any concerns or questions. 10.6 C ONSENT AND ASSENT PROCESS AND DOCUMENTATION The investigational nature and objectives of this trial, the procedures involved, and their attendant risks and discomforts, potential benefits, and potential alternative therapies will be explained to the patient and a signed informed consent obtained. Any experimental invasive procedure will require a separate consent form. All Associate Investigators listed in this protocol who have clinical privileges are permitted to obtain informed consent. For the apheresis for research in the protocol, the patient will consent at the time of the procedures. If the patient refuses the apheresis at that time, the refusal will be documented in the medical record and in the research record. 10.6.1 Telephone Re-Consent Procedure Re-consent on this study may be obtained via te lephone according to the following procedure: the informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. A witness to the subject’s signature will sign and date the consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject’s records. The informed consent process will be documented on a progress note by the consenting investigator and a copy of the informed consent document and note will be kept in the subject’s research record. 10.6.2 Informed Consent of Non-English Speaking Subjects If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the princi pal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 54given to the subject or their legally authorized representative and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to facilitate the conversation (using either the long translated form or the short form). Preferably someone who is independent of th e subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversa tion with the subject (24 to 48 hours if possible). We request prospective IRB approval of the use of the short form process for non-English speaking subjects and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form. 11 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION 11.1 RECOMBINANT FOWLPOX -PSA(L155)/TRICOM  Other Names: PROSTVAC-F/TRICOM ; PROSTVAC-F Classification: Recombinant fowlpox virus vector vaccine of the genus Avipoxvirus. Product Description: Recombinant Fowlpox-PSA(L155)/TRICOM is a recombinant fowlpox virus vector vaccine containing the genes for human PSA and three co-stimulatory molecules (designated TRICOM ): B7.1, ICAM-1 (intercellula r adhesion molecule-1), and LFA-3 (leukocyte function-associated antigen-3). The PSA gene coding sequence is modified to code for a single amino acid substitution [isoleucine to leucine at amino acid position 155 of the PSA antigen (designated L155)], which is designed to enhance immunogenicity. This modification occurs in a 10-mer, HLA-A2-restricted, immunodominant epitope of the antigen [designated PSA-3 (amino acids 154-163)]. An attenuated, live, plaque-purified isolate from the POXVAC-TC strain of fowlpox virus was used as the parental virus for this recombinant vaccine. A plasmid vector containing the modified PSA gene and the genes for the three co-stimulatory molecules is used for in vivo recombination between the plasmid vector and parental fowlpox virus genome. The recombinant vaccine is manufactured by infection of primary chicken embryo dermal (CED) cells with the recombinant fowlpox virus. Fowlpox virus can infect mammalian cells and express the inserted transgenes to stimulate both humo ral and cellular immunity, but cannot replicate in non-avian species, making systemic infections unlikely. 11.1.1 How Supplied Recombinant Fowlpox-PSA(L155)/TRICOM is supplied in vials containing 0.75 mL of the vaccine at a final viral concentration titer of 2 x 109infectious units/mL formulated in phosphate- buffered saline containing 10% glycerol. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 5511.1.2 Preparation Thaw vials completely at room temperature. Ensure the thawed contents are at the bottom of the upright vial and vortex vigorously at high power for at least ten seconds prior to dose preparation. Withdraw 0.5 mL (1 x 109infectious units) into a 1 mL syring e for administration by subcutaneous injection. 11.1.3 Storage Store intact vials of Recombinant Fowlpox-PSA(L155)/TRICOM at –70oC or colder. 11.1.4 Stability Shelf-life stability studies of the intact vials are ongoing. Once the intact vials are thawed, the vaccines maintain their potency for up to 4 days when stored at 2-8oC. Do not re-freeze thawed vials. Vials of Recombinant Fowlpox-PSA(L155)/TRICOM are for single-use only and do not contain a preservative. Administer prepared doses as soon as possible following preparation ( i.e., within one hour). If necessary, store prepared doses at 2-8oC for up to 4 hours following preparation. 11.1.5 Route of Administration Recombinant Fowlpox-PSA(L155)/TRICOM is administered by subcutaneous injection. 11.1.6 Special Handling Fowlpox virus is classified as a Biosafety Level 1 agent. These agents are not known to cause disease in healthy human adults and are of minimal potential hazard to personnel and the environment under ordinary conditi ons of use. Clinicians can use techniques generally acceptable for nonpathogenic material. The recombinant vaccine is a preparation of a live virus (infectious for birds) containing DNA se quences derived from the human genome. Handle the recombinant vaccine as a hazardous biological substance and di spose of waste materials as hazardous biological waste, with incineration according to local institutional policy and according to local, state, and federal regulations. Healthcare workers handling the recombinant fowlpox vaccine should avoid direct contact with pet birds for at le ast 72 hours after working with the agent. Preparation, Handling and Disposal Recommendations 1.