Breast Ductal Carcinoma In Situ
Conditions
Brief summary
This phase II trial studies how well nelipepimut-S plus GM-CSF vaccine therapy or sargramostim works in treating patients with breast cancer. Vaccines made from peptide or antigen and/or a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells that express breast cancer antigens. It is not yet known whether nelipepimut-S plus GM-CSF vaccine or sargramostim is more effective in treating patients with breast cancer.
Detailed description
PRIMARY OBJECTIVE: I. Evaluate for nelipepimut-S-specific cytotoxic T lymphocyte (CTL; cluster of differentiation \[CD\]8+ T cell) response in patients receiving NeuVax (nelipepimut-S plus GM-CSF \[sargramostim\]) compared to patients receiving GM-CSF alone (control). SECONDARY OBJECTIVES: I. Toxicity profile and frequency of adverse events in women with ductal carcinoma in situ (DCIS) of the breast receiving nelipepimut-S vaccine as compared to women receiving GM-CSF alone. II. Presence of DCIS at resection. III. Difference in HER2 expression in the biopsy and the surgical specimen excised post-vaccination. IV. Histologic responses: IVa. Degree of lymphocyte infiltration determined on hematoxylin and eosin (H&E) stained slides and immune infiltration as determined by multiplex immunofluorescence staining for markers including but not limited to CD3, CD4 and CD8. IVb. Immune infiltrates in normal tissue maximally distant from the tumor (in mastectomy samples). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive nelipepimut-S plus GM-CSF vaccine intradermally (ID) on days 0 and 14 and then undergo surgery on day 28. ARM II: Patients receive sargramostim ID on days 0 and 14 and then undergo surgery on day 28. After completion of study treatment, patients are followed up at 1 and 3 months.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGNelipepimut-S Plus GM-CSF Vaccine
Given ID
BIOLOGICALSargramostim
Given ID
PROCEDURESurgical Procedure
Undergo surgery
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must be pre- or post-menopausal * Participants must have a diagnosis of DCIS made by core needle biopsy * Participants must be human leukocyte antigen (HLA)-A2 positive * Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 (Karnofsky \>= 60%) * Clinical chemistry less than 2 x normal upper limit of normal range * Platelets \>= 100,000/mm\^3 * Hemoglobin \>= 10 g/dL * Blood urea nitrogen \< 2 x upper limit of normal (ULN) * Alkaline phosphatase \< 2 x ULN * Lactate dehydrogenase \< 2 x ULN * Creatinine \< 2 x ULN * Bilirubin \< 2 x ULN * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 2 x ULN * A normal ejection fraction, as defined by the participant's institution; only limited echocardiograms (ECHOs) will be used as cardiac evaluation; no other tests are allowed; ECHO is to be done only in HLA-A2 positive participants; if ECHO has been done within 30 days prior to randomization and results showing a normal ejection fraction have been obtained prior to randomization, an additional ECHO is not needed at baseline * Willingness to comply with all study interventions and follow-up procedures * The ability to understand and willingness to sign a written informed consent document
Exclusion criteria
* Invasive breast cancer; areas of microinvasion or suspicious for microinvasion on the core biopsy is allowed * History of prior breast cancer treated within the past two years; patients completing all breast cancer-specific treatment over two years prior to the current diagnosis are eligible * History of prior ductal carcinoma in situ (DCIS) treated within the past two years; patients completing all treatment for a previous diagnosis of DCIS over two years prior to the current diagnosis are eligible * Prior lobular carcinoma in situ (LCIS) is allowed * Pregnant, unwilling to use adequate contraception during study treatment duration or breastfeeding; the effects of NeuVax on the developing human fetus are unknown; for this reason and because NeuVax may be teratogenic, pregnant women will be excluded; all heterosexually active women who may become pregnant must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation OR be post-menopausal defined as any one of the following 1) prior hysterectomy, 2) absence of menstrual period for 1 year in the absence of prior chemotherapy or 3) absence of menstrual period for 2 years in women with a prior history of chemotherapy exposure who were pre-menopausal prior to chemotherapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately * Any autoimmune disease or other medical condition that, in the opinion of the investigator, would compromise the subject's safety * Immune deficiency diseases such as immunoglobulin deficiency or immunosuppressive therapy that might interfere with appropriate immune response * Known history of or known active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C * Patients on chronic steroid therapy or other immunosuppressive therapy except for topical or inhaled steroids known to have low systemic absorption * Patients with a known hypersensitivity to GM-CSF, yeast-derived products, or any component of the GM-CSF product (e.g., mannitol) * Concurrent treatment with other investigational agent * History of non-breast malignancy within 5 years prior to randomization, except curatively treated superficial bladder cancer, carcinoma in situ of the cervix (stage 0-1), and basal cell or squamous cell carcinoma of the skin * History of allergic reactions attributed to compounds of similar chemical or biologic composition to NeuVax * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * No recent or planned immunotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent of Nelipepimut-S-specific Cytotoxic T Lymphocyte Response (E75) | One-Month post-surgical resection from baseline | Change from baseline in the Mean percent of Nelipepimut-S-specific cytotoxic T lymphocyte response one-month post-surgical resection. Wilcoxon rank sum test exact P-value was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) | Baseline to surgical resection, up to 5 weeks | Change from baseline in the iTILs at surgical resection. Wilcoxon rank sum test exact P-value was used. |
| Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) Within the Basement Membrane | Baseline to surgical resection, up to 5 weeks | Change from baseline in the iTILs at surgical resection. Wilcoxon rank sum test exact P-value was used. |
| Number of Participants With HER2 Expression in Biopsy and Resection Specimens | Baseline to surgical resection, up to 5 weeks | Difference in HER2 Expression in Biopsy and Resection Specimens. Differences were assessed using a Fisher's exact test. |
| Number of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03 | 3-6 months after surgery | The number of serious and non serious adverse events for both arms. Graded According to national Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03. |
| Number of Participants With Presence of Ductal Carcinoma in Situ (DCIS) | At resection | Presence of DCIS with Invasive Cancer. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Profile According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03) | up to 3 months after surgery | — |
| Degree of Lymphocyte Infiltration | Up to 6 months after completion of the vaccination series timepoint | We will define intra-tumoral TIL as those within the basement membrane. Stromal TIL will be defined as those in the periductal/lobular stroma including the intralobular stromal infiltrate. Cells in the interlobular stromal inflammatory infiltrate will be excluded. All mononuclear cells will be scored but polymorphonuclear leukocytes will be excluded. Intra-tumoral and stromal TILs will be scored as a continuous variable and the percentage of in the surgical specimen will be compared to that in the pre-vaccination diagnostic biopsy. |
| Immune Infiltrates in Normal Tissue Maximally Distant From the Tumor (in Mastectomy Samples) | Up to 6 months after completion of the vaccination series timepoint | In the mastectomy samples only will perform core needle biopsies of the normal tissue, maximally distant from the tumor (ex vivo after the mastectomy if performed and store for future studies of immune infiltrates. |
| Immune Cell Analysis | up to 6 months after completion of the vaccination series timepoint | Will utilize tissue-based cyclic immunofluorescence (t-CyCIF), a novel, highly multiplexed imaging modality that follows the imaging of formalin-fixed, paraffin embedded (FFPE) tissue sections at subcellular resolution across 20-60 distinct antigen channels. 4-6 panels that will be used include both my not be limited to an already optimized immune panel. |
Countries
United States
Participant flow
Recruitment details
Females \>/= 18 years with DCIS identified on core needle biopsy and at least 1cm area of radiographic abnormality.
Pre-assignment details
Only patients with allele HLA-A2 eligible for randomization. 23-were HLA-A2 negative, 7 were HLA-A2 positive and of the 7: 4-withdrew once they received their results, 1- had disease progression, 1-opted for earlier surgery and 1- opted for earlier surgery when trial went on hold after consent.
Participants by arm
| Arm | Count |
|---|---|
| Arm I GM-CSF Immunoadjuvant GM-CSF | 4 |
| Arm II NPS+GM-CSF Vaccine with immunogenic peptide nelipepimut-S+GM-CSF (NPS+GM-CSF) | 9 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Surgical Pathology | 1 | 0 |
Baseline characteristics
| Characteristic | Arm II NPS+GM-CSF | Total | Arm I GM-CSF |
|---|---|---|---|
| Age, Continuous | 57 years | 57 years | 54.5 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 9 participants | 13 participants | 4 participants |
| Sex: Female, Male Female | 9 Participants | 13 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 9 |
| other Total, other adverse events | 4 / 4 | 9 / 9 |
| serious Total, serious adverse events | 2 / 4 | 0 / 9 |
Outcome results
Primary
Mean Percent of Nelipepimut-S-specific Cytotoxic T Lymphocyte Response (E75)
Change from baseline in the Mean percent of Nelipepimut-S-specific cytotoxic T lymphocyte response one-month post-surgical resection. Wilcoxon rank sum test exact P-value was used.
Time frame: One-Month post-surgical resection from baseline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GM-CSF | Mean Percent of Nelipepimut-S-specific Cytotoxic T Lymphocyte Response (E75) | 0.09 percent of cytotoxic T lymphocytes |
| NPS+GM-CSF | Mean Percent of Nelipepimut-S-specific Cytotoxic T Lymphocyte Response (E75) | 0.02 percent of cytotoxic T lymphocytes |
p-value: 0.71Wilcoxon (Mann-Whitney)
Secondary
Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs)
Change from baseline in the iTILs at surgical resection. Wilcoxon rank sum test exact P-value was used.
Time frame: Baseline to surgical resection, up to 5 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) | 0 percent of iTILs |
| NPS+GM-CSF | Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) | 0 percent of iTILs |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) Within the Basement Membrane
Change from baseline in the iTILs at surgical resection. Wilcoxon rank sum test exact P-value was used.
Time frame: Baseline to surgical resection, up to 5 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF | Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) Within the Basement Membrane | 0 percent of iTILs |
| NPS+GM-CSF | Intra-tumoral Tumor-infiltrating Lymphocytes (iTILs) Within the Basement Membrane | 0.5 percent of iTILs |
p-value: 0.964Wilcoxon (Mann-Whitney)
Secondary
Number of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03
The number of serious and non serious adverse events for both arms. Graded According to national Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03.
Time frame: 3-6 months after surgery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GM-CSF | Number of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03 | Serious Adverse Events | 0 adverse events |
| GM-CSF | Number of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03 | Non Serious Adverse Events | 40 adverse events |
| NPS+GM-CSF | Number of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03 | Serious Adverse Events | 2 adverse events |
| NPS+GM-CSF | Number of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03 | Non Serious Adverse Events | 91 adverse events |
Secondary
Number of Participants With HER2 Expression in Biopsy and Resection Specimens
Difference in HER2 Expression in Biopsy and Resection Specimens. Differences were assessed using a Fisher's exact test.
Time frame: Baseline to surgical resection, up to 5 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection 1+ | 2 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy 3+ | 0 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection 2+ | 1 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy 2+ | 2 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection 3+ | 1 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy Normal Breast Tissue | 0 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection Normal Breast Tissue | 0 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy 1+ | 2 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection Missing | 0 Participants |
| GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy Missing | 0 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection Missing | 2 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy 1+ | 3 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy 2+ | 0 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy 3+ | 3 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy Normal Breast Tissue | 1 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection 1+ | 1 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection 2+ | 1 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection 3+ | 2 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - resection Normal Breast Tissue | 3 Participants |
| NPS+GM-CSF | Number of Participants With HER2 Expression in Biopsy and Resection Specimens | HER2 expression - biopsy Missing | 3 Participants |
p-value: 0.172Fisher Exact
p-value: 0.38Fisher Exact
Secondary
Number of Participants With Presence of Ductal Carcinoma in Situ (DCIS)
Presence of DCIS with Invasive Cancer.
Time frame: At resection
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GM-CSF | Number of Participants With Presence of Ductal Carcinoma in Situ (DCIS) | Not Present | 3 Participants |
| GM-CSF | Number of Participants With Presence of Ductal Carcinoma in Situ (DCIS) | Present | 1 Participants |
| NPS+GM-CSF | Number of Participants With Presence of Ductal Carcinoma in Situ (DCIS) | Not Present | 7 Participants |
| NPS+GM-CSF | Number of Participants With Presence of Ductal Carcinoma in Situ (DCIS) | Present | 2 Participants |
Other Pre-specified
Degree of Lymphocyte Infiltration
We will define intra-tumoral TIL as those within the basement membrane. Stromal TIL will be defined as those in the periductal/lobular stroma including the intralobular stromal infiltrate. Cells in the interlobular stromal inflammatory infiltrate will be excluded. All mononuclear cells will be scored but polymorphonuclear leukocytes will be excluded. Intra-tumoral and stromal TILs will be scored as a continuous variable and the percentage of in the surgical specimen will be compared to that in the pre-vaccination diagnostic biopsy.
Time frame: Up to 6 months after completion of the vaccination series timepoint
Other Pre-specified
Immune Cell Analysis
Will utilize tissue-based cyclic immunofluorescence (t-CyCIF), a novel, highly multiplexed imaging modality that follows the imaging of formalin-fixed, paraffin embedded (FFPE) tissue sections at subcellular resolution across 20-60 distinct antigen channels. 4-6 panels that will be used include both my not be limited to an already optimized immune panel.
Time frame: up to 6 months after completion of the vaccination series timepoint
Other Pre-specified
Immune Infiltrates in Normal Tissue Maximally Distant From the Tumor (in Mastectomy Samples)
In the mastectomy samples only will perform core needle biopsies of the normal tissue, maximally distant from the tumor (ex vivo after the mastectomy if performed and store for future studies of immune infiltrates.
Time frame: Up to 6 months after completion of the vaccination series timepoint
Other Pre-specified
Toxicity Profile According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 4.03)
Time frame: up to 3 months after surgery