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

Study Overview
=================
Brief 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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase I Safety and Immunogenicity Trial of MVA-BN®-HER2 Vaccine in HER-2-Positive Breast Cancer Patients Following Adjuvant Therapy

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Biological: MVA-BN-HER2


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MVA-BN-HER2<br> | Biological: MVA-BN-HER2<br>* experimental vaccine, subcutaneous injection q4weeks x6<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and type of adverse events as a measure of safety and tolerability of multiple vaccinations |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type and duration of immune response measured over time to repeat vaccine administrations |  | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast cancer, Vaccine, Metastatic, HER-2-positive, Phase I, HER-2 Positive Breast Cancer