Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)

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 yeast-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
Tcell subpopulation from that seen with yeast-brachyury vaccine already in development.

Objectives:

To determine the safety and tolerability of escalating doses of MVA-brachyury-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 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, 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 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 equal to 2 x 10^8 infectious
units 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. These cohorts will allow certain standard, relatively non-toxic therapies to
continue while patients receive vaccine.

- Up to 18 patients may be required to be enrolled in the 3 cohorts, plus an additional 10
at the MTD and at the dose level just below it. Thus, up to 38 patients may be
theoretically required to complete this trial. If 3 patients per month can be accrued,
the study is expected to require 1 year to complete the necessary enrollment.

- INCLUSION CRITERIA:

(All Subjects)

1. Patients must have a metastatic or unresectable locally advanced malignant solid
tumor, histologically confirmed by the Laboratory of Pathology, NCI. 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, or
chordoma; other tumors may be included as data on the level of brachyury in those
tumors becomes available).

2. Patients may have measurable or nonmeasurable but evaluable disease. Patients with
surgically resected metastatic disease at high risk of relapse 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 exception of hormonal therapy for prostate and breast cancers,
HER2-directed therapy for HER2+ breast cancer (3+ IHC or FISH+), and erlotinib in
EGFR-mutated lung cancer in the expansion cohort as detailed in section. There should
be a minimum of 6 weeks from any prior antibody therapies, (such as ipilimumab or
anti-PD1/PDL1) due to prolonged half-life.

5. 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.

6. Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of MVA-brachyury-TRICOM vaccine in patients < 18 years
of age, children are excluded from this study but will be eligible for future
pediatric trials.

7. ECOG performance status less than or equal to 1 (Karnofsky greater than or equal to
70%).

8. 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.

- ALT and AST less than or equal to 3 x 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 1,500/mm^3

- Platelet count greater than or equal to 100,000/mm^3

9. Patients must have baseline pulse oximetry > 90% on room air.

10. The effects of MVA-brachyury-TRICOM 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 study
entry and for the duration of study 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 study, she should inform
her treating physician immediately.

11. Patients with prostate cancer must continue to receive GnRH agonist therapy (unless
orchiectomy has been done). If a patient has refused GnRH therapy, they may be
enrolled on a dose level for which the safety has already been determined.

Patients must be able to understand and be willing to sign a written informed consent
document.

INCLUSION CRITERIA:

(Expansion Phase Only)

The following inclusion criteria apply specifically to patients being considered for the
expansion phase of the protocol.

1. Subjects with EGFR-mutated lung cancer may continue erlotinib if they have been on the
drug for greater than or equal to 3 months with stable disease or a response.
Erlotinib may also be continued in the case of a progressing tumor after prior
response (or > 6 months stable disease).

2. Patients with ER+ breast cancer being treated with hormonal therapy (selective
estrogen receptor modulator or aromatase inhibitor) who have rising tumor markers as
evidence of disease progression or metastatic disease on scans may continue on
hormonal therapy while being treated with vaccine.

3. Patients with Her2+ breast cancer receiving Her2-directed therapy (e.g. transtuzumab)
may continue on that therapy when enrolling into a dose level for which safety has
been established.

4. Subjects with metastatic colorectal cancer may continue "mainenance" therapy with
capecitabine and/or bevacizumab.

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 study 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 I.V. 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 study 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 post-intervention 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 MVA-brachyury-TRICOM or other agents used in study.

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 study requirements.

11. Pregnant women are excluded from this study due to the unknown effects of the
MVAbrachyury-TRICOM 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 MVA-brachyury-TRICOM, breastfeeding should be discontinued if the mother
is treated with MVA-brachyury-TRICOM. These potential risks may also apply to other
agents used in this study.

12. HIV-positive patients are ineligible because of the potential for decreased immune
response to the vaccine.