Vaccine Therapy in Preventing Cancer Recurrence in Patients With Non-Metastatic, Node Positive, HER2 Negative Breast Cancer That is in Remission

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and best dose of a vaccine therapy in preventing cancer from coming back in patients with non-metastatic, node positive, human epidermal growth factor receptor (HER)2 negative breast cancer in which all signs and symptoms have disappeared. Vaccines made from deoxyribonucleic acid (DNA) may help the body build an effective immune response to kill tumor cells. Giving multiple vaccinations may make a stronger immune response and prevent or delay the return of cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To assess the safety of 3 escalating doses of a deoxyribonucleic acid (DNA) plasmid based vaccine encoding three breast cancer antigens (insulin-like growth factor-binding protein [IGFBP]-2, HER2, and insulin-like growth factor [IGF]-1 receptor [1R]) in patients with breast cancer. SECONDARY OBJECTIVES: I. To determine the immunogenicity of pUMVC3-IGFBP2-HER2-IGF1R (WOKVAC) T helper cells (Th) polyepitope plasmid based vaccine in patients with breast cancer at 3 escalating doses. II. To determine whether a WOKVAC Th polyepitope plasmid based vaccine elicits a persistent memory T cell response. III. To evaluate whether WOKVAC vaccination modulates T regulatory cells (Treg) and myeloid derived suppressor cells (MDSC). IV. To evaluate changes in mammographic density using clinically available images prior to baseline and post vaccination as an exploratory analysis. V. To determine a recommended phase 2 WOKVAC dose for further breast cancer prevention studies. OUTLINE: This is a dose escalation study of WOKVAC. Patients receive WOKVAC with sargramostim intradermally (ID) on day 1. Courses repeat every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with axillary lymph node dissection (ALND) will have vaccine administered to the contralateral arm. Patients with bilateral ALND will have vaccine administered in the thigh. As much as possible each vaccine dose will be given within the same draining lymph node site. Patients will be monitored for a minimum of 60 minutes post vaccine administration. After completion of study treatment, patients are followed up at 1 month, 6 months and annually for up to 5 years thereafter.

Official Title
-----------------
A Phase I Trial of the Safety and Immunogenicity of a DNA Plasmid Based Vaccine (WOKVAC) Encoding Epitopes Derived From Three Breast Cancer Antigens (IGFBP-2, HER2, and IGF-1R) in Patients With Breast Cancer

Conditions
-----------------
HER2/Neu Negative, No Evidence of Disease, One or More Positive Axillary Nodes, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

Intervention / Treatment
-----------------
* Other: Laboratory Biomarker Analysis
* Biological: pUMVC3-IGFBP2-HER2-IGF1R Plasmid DNA Vaccine
* Biological: Sargramostim


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with non-metastatic, node positive, HER2 negative breast cancer, confirmed by pathology report, who are in remission and defined as having no evidence of disease (NED); HER2 negative is defined as 0-1+ HER2 expression by immunohistochemistry (IHC) OR Fluorescence in situ hybridization (FISH) negative OR HER2 2+ and FISH negative Patients must be at least 28 days post cytotoxic chemotherapy, radiotherapy, monoclonal antibody and/or other biologic therapy, prior to enrollment; patients on bisphosphonates, denosumab, and/or endocrine therapy and may continue throughout duration of study Patients must be at least 28 days post systemic steroids prior to enrollment Patients must have Eastern Cooperative Oncology Group (ECOG) performance status score of =< 2 White blood cell (WBC) >= 3000/mm^3 Hemoglobin (Hgb) >= 10 g/dl Lymphocyte count >= 800/mm^3 Platelet count >= 75,000/mm^3 Serum creatinine =< 2.0 mg/dl or creatinine clearance > 60 ml/min Total bilirubin =< 1.5 mg/dl Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT) =< 2 times upper limit of normal (ULN) Glycosylated hemoglobin measurement (HbA1c) < 5.7% Patients must have recovered from major infections and/or surgical procedures, and in the opinion of the investigator, not have any significant active concurrent medical illnesses precluding protocol treatment Patients who are having sex that can lead to pregnancy must agree to use adequate contraception (hormonal, barrier method of birth control, or abstinence) for the duration of study participation; should a woman become pregnant while participating in the study, she should inform her study doctor immediately and will not receive any more study treatment Left ventricular ejection fraction (LVEF) results must be >= lower limit of normal (LLN) for institution performing based on results from the multi-gated acquisition (MUGA) or echocardiogram (ECHO) done at baseline Willing to not undergo any elective surgical procedure with general anesthesia or conscious sedation through the 1 month post-vaccination visit Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with any of the following cardiac conditions: Symptomatic restrictive cardiomyopathy Dilated cardiomyopathy Unstable angina within 4 months prior to enrollment New York Heart Association functional class III-IV heart failure on active treatment Symptomatic pericardial effusion Patients may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to WOKVAC Patients with any contraindication or known hypersensitivity to receiving sargramostatin (recombinant human granulocyte macrophage colony stimulating factor [rhuGM-CSF]) or other yeast based products Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with this vaccine History of diabetes Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C History of autoimmunity that has not been controlled with treatment in the last 12 months

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

Sexes Eligible for Study
-----------------
All

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (WOKVAC with sargramostim)<br>Patients receive WOKVAC with sargramostim ID on day 1. Courses repeat every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with ALND will have vaccine administered to the contralateral arm. Patients with bilateral ALND will have vaccine administered in the thigh. As much as possible each vaccine dose will be given within the same draining lymph node site. Patients will be monitored for a minimum of 60 minutes post vaccine administration. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: pUMVC3-IGFBP2-HER2-IGF1R Plasmid DNA Vaccine<br>* Given ID<br>* Other names: WOKVAC Vaccine;Biological: Sargramostim<br>* Given ID<br>* Other names: Sargramostatin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity assessed by adverse events per Common Terminology Criteria for Adverse Events version 4.0 | Type and grade of toxicities noted during the immunization regimen will be summarized. Duration of toxicities will also be summarized using descriptive statistics such as mean and standard deviation. The frequency and severity of adverse events will be summarized with a proportion and a 95% confidence interval. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of IgG antibodies | Immune response will be measured by indirect enzyme-linked immunosorbent assay and serum antibody avidity to determine an avidity index before and after vaccination. Patients will be considered to have developed an antibody response if antigen specific IgG antibodies are both detectable and have moderate to high avidity. | Up to 4 months | 
| Assessment of T helper Th1:Th2 ratio | IFN-g (Th1) and IL-10 (Th2) T-cells will be evaluated using enzyme-linked immunosorbent spot assay. Patients will be considered to have developed a Th1 immune response if the ratio of magnitude of Th1 (IFN-gamma)/Th2 (IL-10) is >1. | Up to 4 months | 
| Assessment of the immunogenicity of WOKVAC by generation of IGFBP-2, HER2, and IGF-1R specific type 1 (Th1) T- cells | Immune responses will be measured by IFN-g enzyme-linked immunosorbent spot assay and summarized with mean and standard deviation. Each patient will be given a value at each immune evaluation that is the sum of the median response to HER2, IGFBP-2 or IGF1R, and a composite median would be calculated for each WOKVAC dose level. Patients will be considered to have generated antigen specific (IGFBP-2, HER2, and IGF-1R) Th1 T-cells if they have a ≥1:20,000 composite mean IFN-gamma (IFN-g) precursor frequency by IFN-g enzyme-linked immunosorbent spot assay or greater than 2 fold increase over basel | Up to 4 months | 
| Level of antigen specific central and effector memory phenotypes (Persistent memory T cell response) | Assessed by flow cytometry of peripheral blood mononuclear cells using an established T-cell activation panel and summarized with mean and standard deviation or median and range over time. | Up to 6 months after the last vaccine | 
| Modulation of myeloid derived suppressor cell levels | Assessed by flow cytometry of peripheral blood mononuclear cells using an established myeloid derived suppressor cell/ regulatory T-cell panel and summarized with mean and standard deviation or median and range over time. | Up to 6 months after the last vaccine | 
| Modulation of T regulatory cell levels | Assessed by flow cytometry of peripheral blood mononuclear cells using an established myeloid derived suppressor cell/ regulatory T-cell panel and summarized with mean and standard deviation or median and range over time. | Up to 6 months after the last vaccine | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stage I, Stage II, Stage III