Studying, interpreting, or analyzing de-identified data or specimens for research purposes G. Some/all research activities performed outside NIH Investigational Agents: Drug Name: MVA-brachyury- TRICOM IND Number: 15990 Sponsor: Center for Cancer Research Manufacturer: Bava rian Nordic, Inc. 3 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential PRÉCIS Background: • MVA-brachyury- TRICOM is a novel recombinant vector- based therapeutic cancer vaccine designed to induce an enhanced immune response against brachyury , which is overexpressed in many solid tumor types, such as lung, breast, ovarian, chordoma, prostate, colorectal, and pancreatic adenocarcinoma. • Modified vaccinia Ankara (MVA) is a replication -deficient, attenuated derivative of vaccinia. It is used in the smallpox vaccination and is now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. • Many MVA vector -based trials conducted in patients with cancer have demonstrated its safety and the immunogenicity of its transgenes . • Brachyury is a member of the T -box family of transcription factors. It is overexpressed in cancer cells compared with normal tissue and has been linked to cancer cell resistance and metastatic potential. • Brachyury as a vaccine target has been demonstrated to be safe in an ongoing phase I study of recombinant y east-brachyury and to generate brachyury -specific T -cell responses. • Poxviral vaccines delivering a triad of three human T -cell costimulatory molecules designated TRICOM ( B7.1, ICAM -1 and LFA -3) have been extensively studied in both preclinical and clinical studies and have demonstrated their ability to induce robust T- cell activation and provide evidence of clinical benefit. • In vitro , MVA-brachyury -TRICOM is able to effectively expand brachyury -specific CD8+ and CD4+ T cells from peripheral blood mononuclear cells. • Previous work indicates that MVA-brachyury -TRICOM will induce activation a distinct T - cell subpopulation from that seen with y east-brachyury vaccine already in development. Objectives: • To determine the safety and tolerability of escalating doses of MVA-b rachyury -TRICOM vaccine. Eligibility: • Patients must have histologically confirmed malignancy that is metastatic or unresectable locally advanced malignant solid tumor. In the case of chordoma, unresectable, locally recurrent, or metastatic tumors are acceptable for enrollment, given that this represen ts incurable disease. As much as possible, patients enrolled will have tumor types with known increased expression of b rachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic, or chordoma). • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry • Age ≥ 18 years. • Prior Therapy: Completed , or disease progression on at least one prior line of disease- appropriate therapy for metastatic disease, or not a candidate for therapy of proven efficacy for their disease. 4 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential Design: • This is an open- label, phase I trial with sequential cohorts of patients (3 –6 patients per dose cohort) with dose escalation of MVA-brachyury- TRICOM vaccine. • 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 infectious units (IU) at monthly (28 days +/– 4 days) intervals for 3 months (treatment). • Expansion cohorts of up to 10 patients may be enrolled at the two highest tolerated dose levels.