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)

Background:

- MVA/FPV-Brachyury-TRICOM is a novel recombinant vector-based therapeutic cancer vaccine
comprising a priming vector, Modified Vaccinia Ankara (MVA-brachyury-TRICOM), and a
boost vector, fowlpox (FPV-brachyury-TRICOM), 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.
Fowlpox is also replication incompetent in human cells and can be used for multiple
booster vaccinations due to weak host-neutralizing antibody responses against the
vector.

- 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
Tcell activation and provide evidence of clinical benefit.

- 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.

- A previous phase I trial of MVA-brachyury-TRICOM demonstrated immunogenicity and safety
of the priming dose and established a recommended phase 2 dose. Evaluation was limited
due to the lack of long-term booster dosing.

- This study will evaluate safety and tolerability of MVA-brachyury-TRICOM priming dose
followed by FPV-brachyury-TRICOM booster dose (prime-boost strategy)

Objective:

- To determine the safety and tolerability of MVA-brachyury-TRICOM followed by
FPVbrachyury-TRICOM vaccine.

Eligibility:

- Histologically confirmed malignancy

- 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 represents incurable disease. As much as possible, patients
enrolled will have tumor types with known increased expression of brachyury (such as
lung, breast, ovarian, prostate, colorectal, pancreatic, hepatocellular, Merkel cell,
small cell lung cancer or chordoma).

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry

- Age greater than or equal to 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.

Design:

- This is an open-label, phase I trial. One dose level will be evaluated of
MVA-brachyury-TRICOM priming vaccine followed by fowlpox-brachyury-TRICOM booster
vaccine.

- Up to 10 patients, assuming no more than 1/6 patients experience a dose limiting
toxicity, will be treated with 2 doses of MVA-brachyury-TRICOM priming vaccine
administered subcutaneously with 4 injections of study drug (1 injection = 2 x 10(8)
infectious units (IU) at monthly (28 days +/ 4 days) intervals for 2 months followed by
monthly doses of fowlpox-brachyury-TRICOM at 1 x 109 Infectious units (Inf.U) given as a
single subcutaneous injection monthly (28 days +/- 4 days).

- If 3 patients per month can be accrued, the study is expected to require 3-4 months to
complete the necessary enrollment.

-INCLUSION CRITERIA:

1. Patients must have a histologically confirmed 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
represents incurable disease. Efforts will be made, as much as possible, to enroll
patients with tumor types with known increased expression of brachyury (such as lung,
breast, ovarian, prostate, colorectal, pancreatic, hepatocellular, Merkel cell, small
cell lung cancer or chordoma; other tumors may be included as data on the level of
brachyury in those tumors becomes available). Every attempt will be made to collect
archival tissue, preferably metastatic disease.

2. Patients may have measurable or nonmeasurable but evaluable disease. Patients with
surgically resected metastatic disease at high risk of relapse or patients with
metastatic disease with a complete response after palliative chemotherapy with at high
risk 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 one
prior line of disease-appropriate therapy for metastatic disease, or not be candidates
for therapy of proven efficacy for their disease.

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

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

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

3. Epidermal Growth Factor Receptor-mutated lung cancer patient may remain on first
line Epidermal Growth Factor Receptor inhibiting therapy (tyrosine kinase
inhibitors) if they have had stable disease or ongoing response to therapy.
Patients with T790M mutations may continue receiving osimertinib while receiving
vaccine.

4. Mestastatic colorectal cancer may continue maintenance therapy with capecitabine
and/or bevacizumab.

5. There should be a minimum of 6 weeks from any prior antibody therapies, (such as
ipilimumab or anti-Programmed Death 1/Programmed Death Ligand 1) due to prolonged
half-life.

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

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

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

9. 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 creatinine
clearance on a 24-h urine collection of greater than or equal to 50 mL/min.

- Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) less than or
equal to 3x the upper limits of normal.

- Total bilirubin less than or equal to 1.5 x upper limit of normal OR in patients
with 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 human
fetus are unknown. For this reason, women of child-bearing potential and men must
agree 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 a
period of 4 months after the last vaccination therapy. Should a woman become pregnant
or 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 consent
document.

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 by
these disorders may diminish the effectiveness of this immunologic therapy.

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

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

5. Active autoimmune diseases requiring treatment or a history of autoimmune disease that
might be stimulated by vaccine treatment. This requirement is due to the potential
risks of exacerbating autoimmunity. However, patients with vitiligo or clinically
stable autoimmune endocrine disease who are on appropriate replacement therapy (if
such therapy is indicated) are eligible.

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

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

8. Patients with untreated central nervous system metastases or local treatment of brain
metastases 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 other
eligibility criteria are met.

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

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

11. Pregnant women are excluded from this trial due to the unknown effects of the
BN-Brachyury vaccine on the fetus or infant. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
BN-Brachyury, breastfeeding should be discontinued if the mother is treated with
BN-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 the
potential for decreased immune response to the vaccine.

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