Safety and Tolerability of a Modified Vaccinia Ankara (MVA) Priming Followed by Fowlpox Booster Vaccines Modified to Express Brachyury and T-Cell Costimulatory Molecules (MVA-BN-Brachyury/FPV-Brachyury)

-INCLUSION CRITERIA:

1. Patients must have a histologically confirmed metastatic or unresectable locallyadvanced malignant solid tumor. In the case of chordoma, unresectable, locallyrecurrent, or metastatic tumors are acceptable for enrollment, given that thisrepresents incurable disease. Efforts will be made, as much as possible, to enrollpatients with tumor types with known increased expression of brachyury (such as lung,breast, ovarian, prostate, colorectal, pancreatic, hepatocellular, Merkel cell, smallcell lung cancer or chordoma; other tumors may be included as data on the level ofbrachyury in those tumors becomes available). Every attempt will be made to collectarchival tissue, preferably metastatic disease.

2. Patients may have measurable or nonmeasurable but evaluable disease. Patients withsurgically resected metastatic disease at high risk of relapse or patients withmetastatic disease with a complete response after palliative chemotherapy with at highrisk of relapse (such as small cell lung cancer, etc) are also eligible.

3. Prior therapy: Patients must have completed or had disease progression on at least oneprior line of disease-appropriate therapy for metastatic disease, or not be candidatesfor therapy of proven efficacy for their disease.

4. There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/orradiation, with the following exceptions:

5. Prostate cancer - patients must continue to receive GnRH agonist therapy (unlessorchiectomy has been done). Patients on combined androgen blockade therapy maycontinue those therapies as well (bicalutamide, nilutamide, flutamide,enzalutamide and abiraterone).

6. Breast cancer patients may remain on hormonal therapy if indicated (ER/PR+),HER2-directed therapy for HER2+ breast cancer (3+ IHC or FISH+).

7. Epidermal Growth Factor Receptor-mutated lung cancer patient may remain on firstline Epidermal Growth Factor Receptor inhibiting therapy (tyrosine kinaseinhibitors) if they have had stable disease or ongoing response to therapy.Patients with T790M mutations may continue receiving osimertinib while receivingvaccine.

8. Mestastatic colorectal cancer may continue maintenance therapy with capecitabineand/or bevacizumab.

9. There should be a minimum of 6 weeks from any prior antibody therapies, (such asipilimumab or anti-Programmed Death 1/Programmed Death Ligand 1) due to prolongedhalf-life.

10. Patients must have recovered (grade 1 or baseline) from any clinically significanttoxicity associated with prior therapy. Typically, this is 3 4 weeks for patients whomost recently received cytotoxic therapy, except for the nitrosoureas and mitomycin C,for which 6 weeks is needed for recovery.

11. Age 18 to 85 years. Because no dosing or adverse event data are currently available onthe use of BN-Brachyury vaccine in patients < 18 years of age, children are excludedfrom this trial but will be eligible for future pediatric trials.

12. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%)

13. Patients must have normal organ and marrow function as defined below:

• Serum creatinine less than or equal to 1.5 x upper limit of normal OR creatinineclearance on a 24-h urine collection of greater than or equal to 50 mL/min.

• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) less than orequal to 3x the upper limits of normal.

• Total bilirubin less than or equal to 1.5 x upper limit of normal OR in patientswith Gilbert s syndrome, a total bilirubin less than or equal to 3.0.

• Hematological eligibility parameters (within 16 days of starting therapy):

• Granulocyte count greater than or equal to 1,000/mm(3)

• Platelet count greater than or equal to 100,000/mm(3)

10. The effects of BN-Brachyury (MVA-BN-Brachyury & FPVBrachyury) on the developing humanfetus are unknown. For this reason, women of child-bearing potential and men mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior to trial entry and for the duration of trial participation and for aperiod of 4 months after the last vaccination therapy. Should a woman become pregnantor suspect she is pregnant while she or her partner is participating in this trial,she should inform her treating physician immediately.

11. Patients must be able to understand and be willing to sign a written informed consentdocument.

EXCLUSION CRITERIA:

1. Concurrent treatment for cancer, with specific exceptions noted in inclusion criteria.

2. Chronic hepatitis B or C infection, because potential immune impairment caused bythese disorders may diminish the effectiveness of this immunologic therapy.

3. Any significant disease that, in the opinion of the investigator, may impair thepatient s tolerance of trial treatment.

4. Significant dementia, altered mental status, or any psychiatric condition that wouldprohibit the understanding or rendering of informed consent.

5. Active autoimmune diseases requiring treatment or a history of autoimmune disease thatmight be stimulated by vaccine treatment. This requirement is due to the potentialrisks of exacerbating autoimmunity. However, patients with vitiligo or clinicallystable autoimmune endocrine disease who are on appropriate replacement therapy (ifsuch therapy is indicated) are eligible.

6. Concurrent use of systemic steroids, except for physiologic doses of systemic steroidreplacement or local (topical, nasal, or inhaled) steroid use. Limited pharmacologicdoses of systemic steroids (e.g., in patients with exacerbations of reactive airwaydisease or to prevent intravenous (IV) contrast allergic reaction or anaphylaxis inpatients who have known contrast allergies) are allowed.

7. Patients who are receiving any other investigational agents within 28 days beforestart of trial treatment.

8. Patients with untreated central nervous system metastases or local treatment of brainmetastases within the last 6 months. Patients with stable brain metastasis for 6 months postintervention are eligible.Subjects with chordoma will be eligible regardless of site of disease if othereligibility criteria are met.

9. History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to BN-Brachyury or other agents used in trial. History of allergicreaction to aminoglycoside antibiotics or egg products.

10. Serious or uncontrolled intercurrent illness including, but not limited to, ongoing oractive infection, symptomatic congestive heart failure, unstable angina pectoris,cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion ofthe investigator, would limit compliance with trial requirements.

11. Pregnant women are excluded from this trial due to the unknown effects of theBN-Brachyury vaccine on the fetus or infant. Because there is an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the mother withBN-Brachyury, breastfeeding should be discontinued if the mother is treated withBN-Brachyury. These potential risks may also apply to other agents used in this trial.

12. Human Immunodeficiency Virus (HIV)-positive patients are ineligible because of thepotential for decreased immune response to the vaccine.

13. Patients with a cardiac event within 6 months of the screening visit.