This is optional and not required for enrollment. To be performed within 8 weeks prior to protocol enrollment: • Screening for HIV • Screening for hepatitis B and C. To be performed within 16 days prior to protocol enrollment: • Complete blood count plus differential and platelet count • Serum chemistries (Na+, K+, Cl –, CO 2, glucose, BUN, creatinine, albumin, calcium, magnesium, phosphorus, alkaline phosphatase, ALT, AST, total bilirubin, LDH, TSH) • Urinalysis 31 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential • Beta-HCG for women of child- bearing age (repeated wit hin 48 hours prior to treatment). A female of child -bearing potential (FCBP) is a sexually mature woman who: o Has not undergone a hysterectomy or bilateral oophorectomy o Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 2.3 B ASELINE EVALUATION 2.3.1 Laboratory studies To be performed at any time before protocol enrollment: • HLA typing To be performed within 16 days prior to protocol enrollment: • Screening tests noted above will be used as baseline Additional baseline labs to be performed • ANA titer • CD4:CD8 ratio, CD3, 4, 8, 19 subsets and NK markers (baseline, about day 29 prior to vaccination and around day 85, and then every 85 days thereafter while patients remain on stud y for follow -up) 2.3.2 Electrocardiogram (ECG) within 28 d ays prior to protocol enrollment 2.3.3 Scans and X -rays: To be performed within 28 days prior to the protocol enrollment (may include based on site of disease): • Computerized t omography (CT) of the chest/abdomen /pelvis • Brain MRI • PET scan • Bone scan 2.4 REGISTRATION PROCEDURES Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent. A registration Eligibility Checklist from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm ) must be completed and sent via encrypted email to: NCI Central Registration Office (HOIS) ncicentralregistration - l@mail.nih.gov . After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 32 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential of any investigational agents. Verification of Registration will be forwarded electronically via e - mail to the research team. A recorder is available during non -working hours. 3 STUDY IMPLEMENTATION 3.1 STUDY DESIGN This is an open- label phase I trial with sequential cohorts of patients (3 –6 patients per dose cohort to establish safety ) with dose escalation of MVA-brachyury- TRICOM vaccine (see Section 8). Three cohorts will receive MVA -brachyury -TRICOM vaccine administered subcutaneously as either 1, 2, or 4 injections of study drug (1 injection = 2 x 108 IU) at monthly (28 days– 4 days up to +14 days ) intervals for 3 months (treatment).44 A dose will be considered missed if not given within 14 days of the original schedule and the patient will resume treatment with the next scheduled dose. The time of patient monitoring post injection would be 2 hour observation after first dose and 30 minutes after subsequent doses. Toxicity in the 28 days following the first vaccination after the 3 rd subject (or 6th subject, if applicable) in dose levels 1 through 3 will be employed for decision-making (i.e., for dose- escalation and for maximum tolerable dose estimation). Intrapatient dose escalation will not be allowed. In addition, patients may be enrolled as an expansion cohort at the MTD and at the dose level just below the MTD after either 0 of 3 or no more than 1 of 6 patients have been treated at that dose level and have not experienced a DLT for at least 28 days. Cohorts 2 and 3 will accrue up to an additional 10 evaluable patients each (up to 16 patients total in each ) for safety and correlative analysis. Patients will be sequentially enrolled and monitored for safety as described at dose level 2 and dose level 3. If 0 of 3 or no more than 1 of 6 patients treated at each dose level have experienced a DLT for at least 28 days, we will enroll patients on the expansion phases. Patients may be concurrently enrolled in the expansion cohort of dose level 2 while enrolling patients on dose level 3 for safety evaluation. Any patient who is eligible will be prioritized into a dose escalation slot. Once all dose escalation slots are filled, patients will be enrolled sequentially onto the expansion phase 2, followed by phase 3. Expansion slots will only be filled by subjects who are not eligible (due to concurrent therapy) for escalation slots until safety is established in both dose level 2 and 3. There will not be randomization. Patients who come off study for any reason other than IND- related toxicity (defined as at least possibly related ) prior to completion of the first restaging evaluation (about day 85) may be replaced. If a patient did not experience DLT and did not complete the DLT evaluation period (28 days), he or she will not be evaluable for toxicity and will be replaced in the dose level as outlined in S tatistical Design (Section 8). • If 0/3 patients develop DLT on a dose level, then the dose may be escalated. For purposes of obtaining additional safety and efficacy information, cohorts up to 6 patients /cohort may be enrolled. • If 1/3 patients develops DLT on a dose level, then up to 3 more patients will be enrolled. • If no more than 1/6 patients develops DLT, then the dose will be escalated. 33 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential • If 2 or more patients experience DLT on a dose level, then the MTD has been exceeded and dose escalation has been completed. Three patients will be enrolled on the dose level below that level, provided that not more than 3 patients were treated on that dose level. (The MTD will be the dose level at which no greater than 1/6 patients has a DLT, and the next higher dose level has at least 2 patients with a DLT.) 3.1.1 Dose -Limiting Toxicity Dose -limiting toxicity will be defined as any one of the following: Any grade ≥ 3 hematologic toxicity or grade ≥ 3 non- hemato logic toxicity that is possibly, probably, or definitely related to study drug, except transient (≤ 48 hour) grade 3 fatigue, local reactions, flu- like symptoms, fever, headache, and laboratory abnormalities that are not associated with organ pathology. Also any ≥ grade 2 allergic and ≥ grade 2 autoimmune reaction(s) (except endocrine- related immune toxicity) will be defined as a DLT. Any grade 3 autoimmune endocrine- related toxicity that has not resolved clinically within 7 days of initiating therapy will also be defined as a DLT. Generalized erythroderma or macular or papular rash lasting less than 7 days and not associated with desquamation will not be DLT s. In addition, study accrual will be halted pending discussions with the IRB and the study sponsor if there is an occurrence of a grade 5 toxicity by the NCI -CTCAE (Version 4) attributable to the treatment regimen or if the maximum tolerated dose (MTD) is exceeded in dose level 1. 3.1.2 DLT Evaluation P eriod The evaluation period for DLT s will be 28 days fol lowing the first injection of vaccine. 34 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential 3.1.3 Schema Dose Level Dose and Schedule 1 N = 3 to 6 1 site of injection at 2 x 108 IU given every 28 days for 3 doses. 2 N = 10-16 2 site s of injection at 2 x 108 IU given every 28 days for 3 doses. 3 N = 10-16 4 sites of injection at 2 x 108 IU given every 28 days for 3 doses. Dose escalation will proceed in cohorts of 3–6 patients. The MTD is the dose level at which no more than 1 of up to 6 patients have DLT during the first 28 days of treatment, an d the dose below that at which at least 2 (of ≤ 6) patients have DLT as a result of the drug. If a patient did not experience DLT and did not complete the DLT evaluation period (28 days), he or she will not be evaluable for toxicity and will be replaced in the dose level as outlined in the S tatistical Design (Section 8). Dose escalation will follow the rules outlined in the table below. 35 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential Number of Patients with DLT at a Given Dose Level Escalation Decision Rule 0 of 3 Enter up to 3 patients at the next dose level > 2 Dose escalation will be stopped. This dose level will be declared the maximally administered dose (highest dose administered). Up to t hree (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose. 1 of 3 Enter up to 3 more patients at this dose level. • If 0 of these 3 patients experience DLT, proceed to the next dose level. • If 1 or more of this group experience DLT, then dose escal ation is stopped, and this dose is declared the maximally administered dose. Up to t hree (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose. < 1 of 6 at highest dose level below the maximally administered dose This is the MTD and is g enerally the recommended phase II dose. At least 6 patients must be en tered at the recommended phase II dose. 3.2 DRUG ADMINISTRATION MVA-brachyury-TRICOM is supplied frozen in single-use vials. The via l must be thawed at room temperature for approximately 10-15 minutes prior to preparation, and should not be re- frozen after thawing. The thawed suspension will appear milky and may contain clumps or aggregates. T o ensure homogeneity, the vial should be swirled vigorously, but not shaken, for approximately 10 – 20 seconds immediately prior to use. The thawed drug product is to be drawn into a syringe with an appropriately sized safety shielded needle suited to patient comfort (e.g.