HER2/Neu Negative, No Evidence of Disease, One or More Positive Axillary Nodes, Stage IB Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage III Breast Cancer, Stage IIIC Breast Cancer
Conditions
Keywords
Stage I, Stage II, Stage III
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
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
Given ID
BIOLOGICALSargramostim
Given ID
Sponsors
National Cancer Institute (NCI)
University of Wisconsin, Madison
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 administered during the study are eligible 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) * 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 * The effects of WOKVAC on the developing human fetus are unknown. For this reason, 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 sargramostim (recombinant human granulocyte macrophage colony stimulating factor \[rhuGM-CSF\]) or other yeast based products * Pregnant women are excluded from this study because WOKVAC is a vaccine agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with WOKVAC 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Up to 9 months | Toxicities by grade that were related (possibly, probably or definitely) to the study vaccine noted during the immunization regimen will be summarized. This is done by arm, Grade and Attribution to study vaccine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of IgG Antibodies | Up to 4 months | 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. |
| Assessment of T Helper Th1:Th2 Ratio | Up to 9 months | 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 as the sum IFN-Ɣ magnitude from all antigens to maximum response. This will be presented as a median fold change from baseline to the maximum response (1 or 6 months after vaccination). |
| Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | Up to 24 weeks | Immune responses will be measured by IFN-g enzyme-linked immunosorbent spot assay using blood (PBMC) represented by a maximum immune response generated to each antigen individually measured as corrected spots per well (cSPW). At the immune evaluations, each patient was given a value to indicate their immune response at both baseline and post vaccination. This data is represented by a median response, at both baseline (before vaccination) and 1 month or 6 months after the last vaccination of 3 vaccines (maximum response), to each of the 3 vaccine antigens HER2, IGFBP-2 or IGF1R. |
| Level of Antigen Specific Central and Effector Memory Phenotypes (Persistent Memory T Cell Response) | Up to 6 months after the last vaccine | 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. |
| Modulation of Myeloid Derived Suppressor Cell Levels | Up to 24 weeks | 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. |
| Modulation of T Regulatory Cell Levels | Up to 24 weeks | Assessed by flow cytometry of peripheral blood mononuclear cells using an established myeloid derived suppressor cell/ regulatory T-cell panel and summarized with median and range. FOXP3 is used to identify regulatory T cells, specifically CD4+ cells isolated from PBMC. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim 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.
Laboratory Biomarker Analysis: Correlative studies
pUMVC3-IGFBP2-HER2-IGF1R Plasmid DNA Vaccine: Given ID
Sargramostim: Given ID | 10 |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim 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.
Laboratory Biomarker Analysis: Correlative studies
pUMVC3-IGFBP2-HER2-IGF1R Plasmid DNA Vaccine: Given ID
Sargramostim: Given ID | 12 |
| Reatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim 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.
Laboratory Biomarker Analysis: Correlative studies
pUMVC3-IGFBP2-HER2-IGF1R Plasmid DNA Vaccine: Given ID
Sargramostim: Given ID | 10 |
| Total | 32 |
Baseline characteristics
| Characteristic | Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Reatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Total |
|---|---|---|---|---|
| Age, Continuous | 51 years | 53 years | 45 years | 51.9 years |
| Race/Ethnicity, Customized Asian - Unknown | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown - Unknown | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Non Hispanic Latino | 10 Participants | 10 Participants | 8 Participants | 28 Participants |
| Race/Ethnicity, Customized White - Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Canada | 2 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 8 participants | 12 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 9 Participants | 31 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 1 / 12 | 1 / 10 |
| other Total, other adverse events | 10 / 10 | 12 / 12 | 10 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 12 | 0 / 10 |
Outcome results
Primary
Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0
Toxicities by grade that were related (possibly, probably or definitely) to the study vaccine noted during the immunization regimen will be summarized. This is done by arm, Grade and Attribution to study vaccine.
Time frame: Up to 9 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Grade 1 related adverse events | 45 Count of Related Adverse Events per Arm |
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Grade 2 related adverse events | 2 Count of Related Adverse Events per Arm |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Grade 1 related adverse events | 53 Count of Related Adverse Events per Arm |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Grade 2 related adverse events | 1 Count of Related Adverse Events per Arm |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Grade 1 related adverse events | 30 Count of Related Adverse Events per Arm |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Number of Adverse Events Per Common Terminology Criteria for Adverse Events Version 4.0 | Grade 2 related adverse events | 7 Count of Related Adverse Events per Arm |
Secondary
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.
Time frame: Up to 4 months
Secondary
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 using blood (PBMC) represented by a maximum immune response generated to each antigen individually measured as corrected spots per well (cSPW). At the immune evaluations, each patient was given a value to indicate their immune response at both baseline and post vaccination. This data is represented by a median response, at both baseline (before vaccination) and 1 month or 6 months after the last vaccination of 3 vaccines (maximum response), to each of the 3 vaccine antigens HER2, IGFBP-2 or IGF1R.
Time frame: Up to 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | HER2 - Baseline | 92 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | HER2 - Maximum | 639 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGF-1R - Baseline | 0 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGF-1R - Maximum | 0 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGFBP-2 - Baseline | 58.5 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGFBP-2 - Maximum | 184.5 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGFBP-2 - Maximum | 215 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | HER2 - Baseline | 109 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGF-1R - Maximum | 18 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGFBP-2 - Baseline | 179 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | HER2 - Maximum | 203 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGF-1R - Baseline | 0 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | HER2 - Maximum | 237.5 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGF-1R - Baseline | 107 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGFBP-2 - Maximum | 207.5 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGF-1R - Maximum | 76 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | HER2 - Baseline | 402 correct spots per well (cSPW)/10^6 PBMC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of the Immunogenicity of WOKVAC by Generation of IGFBP-2, HER2, and IGF-1R Specific Type 1 (Th1) T- Cells | IGFBP-2 - Baseline | 123 correct spots per well (cSPW)/10^6 PBMC |
Secondary
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 as the sum IFN-Ɣ magnitude from all antigens to maximum response. This will be presented as a median fold change from baseline to the maximum response (1 or 6 months after vaccination).
Time frame: Up to 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Assessment of T Helper Th1:Th2 Ratio | 3.5 score on a scale |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Assessment of T Helper Th1:Th2 Ratio | 4.5 score on a scale |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Assessment of T Helper Th1:Th2 Ratio | 1.2 score on a scale |
Secondary
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.
Time frame: Up to 6 months after the last vaccine
Secondary
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.
Time frame: Up to 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Modulation of Myeloid Derived Suppressor Cell Levels | 0.00 percentage of m-MDSC |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Modulation of Myeloid Derived Suppressor Cell Levels | 0.00 percentage of m-MDSC |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Modulation of Myeloid Derived Suppressor Cell Levels | 0.01 percentage of m-MDSC |
Secondary
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 median and range. FOXP3 is used to identify regulatory T cells, specifically CD4+ cells isolated from PBMC.
Time frame: Up to 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (WOKVAC With Sargramostim) - Dose 150 mcg + 100 mcg Sargramostim | Modulation of T Regulatory Cell Levels | 8 % of Foxp3+ cells among CD4+ cells |
| Treatment (WOKVAC With Sargramostim) - Dose 300 mcg + 100 mcg Sargramostim | Modulation of T Regulatory Cell Levels | 5 % of Foxp3+ cells among CD4+ cells |
| Treatment (WOKVAC With Sargramostim) - Dose 600 mcg + 100 mcg Sargramostim | Modulation of T Regulatory Cell Levels | 4 % of Foxp3+ cells among CD4+ cells |