Treatment of Castration Resistant Prostate Cancer Using Multi-Targeted Recombinant Ad5 PSA/MUC1/Brachyury Based Immunotherapy Vaccines

Background: * The overall goal of the current project is to expand our immunotherapeutic approach for the treatment of prostate cancer employing a multi-targeted approach. * Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors. * A novel adenovirus based vaccines targeting three (3) human tumor associated antigens (TAA), Prostate specific antigen (PSA), Mucin 1 (MUC1), and brachyury, respectively have demonstrated anti-tumor cytolytic T cell responses in pre-clinical animal models of cancer. Objectives: -To determine the overall safety and recommended phase 2 dose of a combination of three immunotherapeutic vaccines (ETBX-071, ETBX-061, and ETBX-051) when administered subcutaneously (SC) to subjects with metastatic castration resistant prostate cancer Eligibility: * Subjects age 18 and older with cytologically or histologically confirmed prostate cancer for which no curative standard approved therapy is available. * Metastatic Castration Resistant Prostate Cancer (mCRPC) patients with rising PSA or progressive disease despite castration levels of testosterone. * Prior treatment with immunotherapy hormonal therapy, radiotherapy, chemotherapy, and/or other experimental therapy is allowed. * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 * Adequate organ and bone marrow function * Subjects with a history of autoimmune disease (active or past) and subjects requiring systemic steroids are not eligible (physiologic doses of steroids for steroid replacement as well as nasal, topical and inhaled steroids are allowed). Autoimmune-related thyroid disease, type I diabetes and vitiligo are permitted if the condition is well controlled. Design: * This is a Phase I trial in subjects with mCRPC. A combination of three therapeutic vaccines (ETBX-071, ETBX-061, and ETBX-051) which use the same modified Adenovirus vector backbone, separately encoding three well studied TAA,PSA, MUC1, and brachyury, respectively) will be assessed. The vaccines will be tested at standard dose levels, with a dose de-escalation (if required) design employed. The dose level of each vaccine tested will be 5x10 to the eleventh power VP. This dose has been found in a prior phase 1 testing of a similar vaccine Ad5 \[E1-, E2b-\]-carcinoembryonic antigen (CEA)(6D) (ETBX-011) to be well tolerated (with no dose-limiting toxicities (DLTs) or related serious adverse events(SAEs), and be optimal for induction of immune responses. * Up to six patients will be enrolled at dose level 1. If less than or equal to 1 of 6 patients experience a DLT, an initiation of the dose expansion phase will occur. If more than or equal to 2 of 6 experience DLT at dose level 1, then dose de-escalation will occur. Up to six patients will be enrolled at the lower dose level (-1) (1x10 to the eleventh power VP). If less than or equal to 1 of 6 patients experience a DLT, then the maximum tolerated (MTD) will be declared at this dose, and initiation of the dose expansion phase will occur. If more than or equal to 2 of 6 experience DLT at dose level -1, then a further dose de-escalation will occur. Up to six patients will be enrolled at the lower dose level (-2) (5x10 to the tenth power VP). If less than or equal to 1 of 6 patients experience a DLT, then the maximum tolerated (MTD) will be declared at this dose, and initiation of the dose expansion phase will occur. If more than or equal to 2 of 6 experience DLT at dose level -2, then the study will be stopped. * A dose expansion phase of study will be enrolled after the MTD of the vaccines have been determined. An additional 12 subjects will be enrolled in the dose expansion component of the trial, for a total of 18 subjects at the MTD. * The ETBX-051, ETBX-61 and ETBX-71 vaccines will be administered subcutaneously (SC) at separate injection sites (proximal limb, preferably the thigh), will be administered SC every 3 weeks for 3 doses (dose de-escalation cohorts) followed by boosts every 8 weeks for 1 year (only patients enrolled in dose expansion cohort).