A Safety and Immunology Study of a Modified Vaccinia Vaccine for HER-2(+) Metastatic Breast Cancer

MVA-BN®-HER2 is a candidate breast cancer immunotherapy product comprised of a highly
attenuated non-replicating vaccinia virus, MVA-BN®, engineered to encode a modified form of
the Her-2 protein.

MVA-BN® is a well-characterized, clonal strain of modified vaccinia virus Ankara (MVA) being
developed as a smallpox vaccine, suitable for use in high-risk (e.g., immunocompromised)
individuals. MVA-BN®-derived vectors encoding heterologous antigens are being developed for
use as vaccines for infectious diseases such as HIV, and for the treatment of cancer. A large
database exists from safety evaluations in animals and in humans for MVA-BN®, and
MVA-BN®-derived vectors.

Her-2 is overexpressed in 20-30% of human breast cancers. It is an oncogene/growth factor
receptor critical for malignant phenotype of Her-2 expressing tumors. It is an immunogenic
target, and immune responses to this protein have been shown to mediate potent anti-tumor
activity in multiple animal models. Means to stimulate anti-Her-2 reactivity are now being
studied clinically. Sponsor, collaborators, and others have used both Protein and DNA vaccine
forms of Her-2, and a safety database is developed and no significant adverse events have
resulted from Her-2 directed vaccination.

MVA-BN®-HER2 encodes a modified form of the Her-2 protein, hereinafter referred to as HER2.
HER2 contains the extracellular domain of Her-2 but lacks the intracellular, cell signaling
domain. In addition, HER2 includes two universal T-cell epitopes from tetanus toxin to
facilitate the stimulation of an immune response to Her-2, a self-protein.

The current trial, BNIT-BR-002, will evaluate the safety and biological activity of a fixed
dose of MVA-BN®-HER2, with and without Herceptin, following 1st- or 2nd-line chemotherapy in
patients with metastatic breast cancers which overexpress Her-2.

Patients will receive 3 subcutaneous vaccinations at 3 week intervals and have tumor followed
by CT/MRI imaging and blood drawn for immune function analysis.

Inclusion Criteria:

- Signed Informed Consent

- Women, ≥ 18 years of age

- Histologically documented, HER-2 (+) breast cancer with metastatic disease.

- Evaluable or measurable disease. PATIENTS MAY BE NED. Patients must be assessed as
having stable disease or better at the end of 1st- or 2nd-line chemotherapy. In
addition, patients must have a tumor assessment within 28 days of the first planned
dose of MVA-BN®-HER2, and have a response status of SD or better.

- Prior chemotherapy for metastatic breast cancer

- Completed 1st- or 2nd-line chemo for mBrCA at least 3 weeks (from the date of the last
dose) prior to the first dose of MVA-BN®-HER2

- ECOG Performance Score of 0, 1, or 2

- Life expectancy ≥ 6 months

- Left ventricular ejection fraction (LVEF) by ECHO or MUGA ≥ LLN

- Women of childbearing potential must have a negative serum or urine pregnancy test,
and must agree to use a medically acceptable barrier and/or chemical method of
contraception throughout the study treatment period and for 28 days after the last
dose of MVA-BN®-HER2

- No significant cardiac, bone marrow dysfunction, or coagulopathy. No significant
hepatic or renal dysfunction.

- A negative virology screen for HIV, hepatitis B surface antigen, hepatitis C, and
HTLV-1

Exclusion Criteria:

Patients may not have:

- Known history of metastasis to the central nervous system

- Congestive heart failure (NYHA Class III or IV), unstable angina, or cardiovascular
disease such as stroke or myocardial infarction (current or within the past 6 months)

- History of prior malignancies other than breast cancer within the past 5 years,
excluding basal or squamous cell carcinoma of the skin or carcinoma in situ of the
cervix

- Known allergy to eggs, egg products, or aminoglycoside antibiotics, e.g., gentamicin
or tobramycin

- Chronic administration (5 or more consecutive days) of systemic corticosteroids within
14 days of the first planned dose of MVA-BN®-HER2.

- History of or active autoimmune disease. Persons with vitiligo or thyroid disease
taking thyroid replacement hormones are not excluded.

- Prior solid organ or hematopoietic allogenic transplant(s)

- Prior use of hematopoietic growth factors (e.g., GM-CSF) within 28 days of the first
planned dose of MVA-BN®-HER2

- Receipt of an investigational agent within 28 days of the first planned dose of
MVA-BN®-HER2

- Prior "vaccine" therapy for breast cancer at any time

- Vaccination: Vaccinations with a live (attenuated) vaccine within 28 days of the first
or last dose of study drug; or vaccinations with a killed (inactivated) vaccine within
14 days of the first or last dose of study drug.

- A maximum cumulative dose of prior doxorubicin > 360 mg/m2 or epirubicin > 720 mg/m2

- Radiation therapy within 28 days of the first planned dose of MVA-BN®-HER2 or plans
for radiation therapy after enrollment.

- Pregnant, lactating, or nursing

- Any condition which, in the opinion of the investigator, would prevent full
participation in this trial or the long-term follow-up study, or would interfere with
the evaluation of the trial endpoints