Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS and to the Sponsor. The principal investigator will review adverse event and resp onse data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff. 7.6.2 Sponsor Monitori ng Plan This trial will be monitored by personnel employed by Harris Technical Services on contract to the NCI, NIH. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct. At least 25% of enrolled patients will be randomly selected and monitored at least biannually or as needed, based on accrual rate. The patients selected will have 100% source document verification done. Additional monitoring activities will include: adherence to protocol specified study eligibility, treatment plans, data collection for safety and efficacy, reporting and time frames of adverse events to the NCI IRB and FDA, and informed consent requirements. Writt en reports will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 7.6.3 Safety Monitoring Committee (SMC) This protocol will require oversight from the S afety 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 there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 51 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential 8 STATISTICAL CONSIDERATIONS This study will be conducted as a standard phase I trial with an expanded cohort at the MTD. There are 3 dose levels of vaccine to be evaluated, and initially 3 patients will be enrolled in the lowest dose level. If 0/3 have a dose limiting toxicity (DLT) after 28 days from the third patient receiving the initial vaccine on study, then subsequent patients will be accrued to the next higher dose level. If 1/3 has a DLT, then 3 additional patients will be enrolled at that dose level. If 1/6 has a DLT, escalation may proceed, while if 2+/6 have a DLT, then the MTD will be considered to have been exceeded, and up to 3 additional patients will be enrolled at the next lower dose level if 6 patients have not previously been enrolled at that dose. 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. The MTD will initially consist of 6 patients as indicated, and the study plans to enroll a total of 10 additional patients each at the MTD and the dose level below MTD (total of 16 at the MTD and up to 16 at the dose level just below the MTD) in in an effort to identi fy significant changes in T-cell precursors will be detectable. Potential evaluation techniques include flow- cytometry based intracellular cytokine staining after bBrachyury 15-mer stimulation and ELISPOT. Evaluations will take place both with respect to absolute change as well as whether a positive response is identified. Because we will be using new evaluation techniques with a first in human study, we will enroll 10 patients in an expansion cohort, resulting in 16 potential evaluable patients in the t wo highest tolerated dose level cohort s, which will provide 80% power to detect a change in T- cell precursors from baseline equal to 1.0 standard deviations of the difference (effect size = 1.0) using a 2-tailed 0.05 alpha level paired t- test. All 10 -16 patients in each dose level with evaluable T -cell precursor data at this dose level will be included in the analysis, with 10 patients providing an illustration of 80% power based on that minimal number. The actual power could be greater than 80% if 11-16 patients are evaluable for this determination. In practice, a nonparametric Wilcoxon signed rank test will be used. A positive response using the flow based intracellular cytokine staining assay will be defined as the frequency of T lymphocytes positive for a cytokine or CD107a post- vaccine being increased greater than two-fold compared to both (1) pre -vaccine values and (2) HLA control post-vaccine; the fraction of the patients who have a positive response out of those evaluable for this determination will be noted and reported along with a corresponding 95% confidence interval. Although the MTD will have been declared after 6 patients at that dose level have been evaluated, monitoring for toxicity in the additional cohort of patients will continue. In the event that more than one third of all patients enrolled at the MTD experience a DLT, protocol modifications will be undertaken to reduce the likely level of toxicity in future patients prior to continuing to enroll additional subjects. Clinical response evaluation will take place in the patients enrolled at the MTD and the expansion cohort. The results will be considered secondary and will be used to determine the parameters for a subsequent phase II trial should the preliminary findings from this trial wa rrant further investigation. 52 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential Up to 18 patients may be required to be enrolled in the 3 cohorts, plus an additional 10 at the MTD and the next highest dose level. Thus, up to 38 patients may be theoretically required to complete this trial. If 3 patients p er month can be accrued, the study is expected to require 1 year to complete the necessary enrollment. 9 COLLABORATIVE AGREEMENTS 9.1 AGREEMENT TYPE The MVA -brachyury -TRICOM vaccine is being provided by Bavar ian Nordic, Inc. under a Collaborative Research and Development Agreement (CRADA) with LTIB, CCR.