a safety and immunology study of a modified vaccinia vaccine for her-2(+) metastatic breast cancer

Conditions: Breast Cancer

Summary: 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 her-2-positive metastatic breast cancer. the intent of vaccination is to induce anti-her-2 immune responses, both antibody and t cell, that will then attack the her-2 expressing tumors, and may induce tumor regression or slow progression of disease.

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.

Eligibility criteria:
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

Keywords: breast cancer vaccine metastatic her-2-positive phase i her-2 positive metastatic breast cancer