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

Conditions: Breast Cancer

Summary: the current trial, bnit-br-003, will evaluate the safety and biological activity of a fixed dose of mva-bn®-her2 following adjuvant chemotherapy in patients with her-2-positive breast cancer. the intent of vaccination is to induce a combined antibody and t-cell anti-her-2 immune response, which is intended to target her-2-expressing tumor cells, 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 the 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-003, will evaluate the safety and biological activity of a fixed dose of mva-bn®-her2 following adjuvant chemotherapy in patients with breast cancers which overexpress her-2. patients will receive 6 subcutaneous vaccinations at 4-week intervals and will have blood drawn for immune function analysis.

Eligibility criteria:
inclusion criteria: * signed informed consent * women, ≥ 18 years of age * histologically documented, her-2-positive breast cancer without metastatic disease. hormone receptor (er/pr) status may be either positive or negative. her-2 (+) status may be determined by one of the following measurements: * immunohistochemistry 3+ or fish/cish+ (her-2 gene signal to centromere 17 signal \> 2). note: her-2 assessment may have been on initial diagnosis and need not be repeated. * patients should be assessed as having no evidence of disease (ned) at the end of adjuvant chemotherapy. in addition, these patients must have a clinical evaluation and lab work as standard of care disease assessment without evidence of recurrence within 28 days of the first planned dose of mva-bn®-her2. * completed adjuvant and/or neoadjuvant chemotherapy for breast cancer at least 3 months previously (measured from the date of the last dose of chemotherapy) and prior to the first planned dose of mva-bn®-her2). * ecog performance score of 0, 1. * predicted life expectancy ≥ 12 months * left ventricular ejection fraction (lvef) by echo ≥ lln as defined by institutional standards * 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 (defined as no grade 3 or greater ae according to nci ctcae v 3.0). no significant hepatic or renal dysfunction (defined as no grade 2 or greater ae according to nci ctcae v 3.0. patients with a known history of a clinically non-significant laboratory parameter may be eligible for inclusion provided an exemption is granted by the study medical monitor prior to enrollment. * a negative virology screen for hiv, hbsag, and hcv exclusion criteria: * 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 cardiac toxicity secondary to chemotherapy or herceptin immunotherapy (lvef decline of 15% or greater from baseline) * 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 * any breast cancer metastases beyond the lymph nodes * known allergy to eggs, egg products, or aminoglycoside antibiotics, e.g., gentamicin or tobramycin * chronic administration (defined as 6 or more consecutive days of use) of systemic corticosteroids within 14 days of the first planned dose of mva-bn®-her2. limited use of inhaled steroids, nasal sprays, eye drops, and topical creams for small body areas is allowed. * 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 14 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: live (attenuated) vaccine (e.g., flumist®) vaccination with a live vaccine within 28 days of the first planned dose of mva-bn®-her2, or plans to receive a live vaccine within 28 days after the last dose of mva-bn®-her2 is not allowed killed (inactivated) vaccine (e.g.,pneumovax®) vaccination with a killed vaccine within 14 days of the first planned dose of mva-bn®-her2, or plans to receive a killed vaccine within 14 ' days after the last dose of mva-bn®-her2 is not allowed * a maximum cumulative dose of prior doxorubicin \> 360 mg/m2 or epirubicn \> 720 mg/m2 * radiation therapy within 14 days of the first planned dose of mva-bn®-her2 or plans for radiation therapy after enrollment. prior to initiating palliative radiation during the treatment phase of the study, the sponsor's medical monitor or designee must be contacted. * 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 breast cancer