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

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

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 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.

Official Title
-----------------
A Phase I Trial of a Fixed Dose of MVA-BN-HER2 Following 1st- or 2nd-Line Chemotherapy for HER-2-Positive Metastatic Breast Cancer

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 (+) 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

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: MVA-BN-HER2|Experimental vaccine, subcutaneous injection q3weeks x 3|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability |  | 2years, 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune response |  | 2 yrs 3 mo | 

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