Nelipepimut-S Plus GM-CSF Vaccine Therapy in Treating Patients With Breast Cancer

• ClinicalTrials.gov Identifier: NCT02636582
• Recruitment Status: Active, not recruiting
• First Posted: December 22, 2015
• Last Update Posted: July 2, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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. It is not yet known whether nelipepimut-S plus GM-CSF vaccine or sargramostim is more effective in treating patients with breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Ductal Carcinoma In Situ	Other: Laboratory Biomarker Analysis; Drug: Nelipepimut-S Plus GM-CSF Vaccine; Biological: Sargramostim; Procedure: Surgical Procedure	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: VADIS Trial: Phase II Trial of Nelipeimut-S Peptide Vaccine in Women With DCIS of the Breast
• Actual Study Start Date: June 14, 2016
• Actual Primary Completion Date: July 22, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (nelipepimut-S plus GM-CSF vaccine); Patients receive nelipepimut-S plus GM-CSF vaccine ID on days 0 and 14 and then undergo surgery on day 28.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Nelipepimut-S Plus GM-CSF Vaccine; Given ID; Other Names: E75 Plus GM-CSF; E75 Vaccine Plus GM-CSF; HLA A2/A3-Restricted HER-2/neu Peptide Vaccine Plus GM-CSF; Nelipepimut-S Plus Sargramostim; NeuVax Plus GM-CSF; Procedure: Surgical Procedure; Undergo surgery; Other Names: Operation; Surgery; Surgical; Surgical Intervention; Surgical Interventions; Surgical Procedures; Type of Surgery
Active Comparator: Arm II (sargramostim); Patients receive sargramostim ID on days 0 and 14 and then undergo surgery on day 28.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Sargramostim; Given ID; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin; Procedure: Surgical Procedure; Undergo surgery; Other Names: Operation; Surgery; Surgical; Surgical Intervention; Surgical Interventions; Surgical Procedures; Type of Surgery

Outcome Measures

Primary Outcome Measures :

1. Change in the number of nelipepimut-S-cytotoxic T lymphocytes (CTL), detected using a dextramer assay [ Time Frame: Pre-vaccination to up to 1 month after surgery ]
   Change of nelipepimut-S-specific CTL at the 1 month (+/- 7 days) after completion of the vaccination series timepoint from baseline will be estimated for each group using mean, standard deviation, median, minimum and maximum. Two-sample t-test or Wilcoxon rank sum test, whichever appropriate, will be used to compare the change between the two groups. Nelipepimut-S-specific CTL will also be measured repeatedly through 6 months after the last vaccination. Repeated measures analysis including mixed effects model will be performed to analyze the effect of treatment on nelipepimut-S-specific CTL change over time.

Secondary Outcome Measures :

1. 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 ]
   Compared between the two groups. Adverse events by grade and relationship will be summarized by tabulation for each group.
2. Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.03 [ Time Frame: Up to 3 months after surgery ]
   Adverse events by grade and relationship will be summarized by tabulation for each group.
3. Presence of ductal carcinoma in situ (DCIS) [ Time Frame: At resection ]
   The histologic data will be presented in tabular form to examine whether the vaccine treatment is associated with the absence of DCIS, induction of necrosis, reduction in histologic grade, or a reduction in the size of DCIS. These data will be descriptive only. The data will be obtained from the standard surgical pathology report generated as part of the patient's clinical care. Formal comparisons of these parameters would likely require a larger sample size to see a statistically significant difference in presence of DCIS, induction of necrosis, or reduction in size of DCIS.
4. Difference in HER2 expression [ Time Frame: In the biopsy and the surgical specimen excised post-vaccination ]
   HER2 scoring will be determined according to the American Society of Clinical Oncology/College of American Pathologists clinical guidelines. Positive cases are those with circumferential membrane staining that is complete, intense, and within > 10% of tumor cells (score 3+). Negative cases are defined as those with no observable staining, or membrane staining that is incomplete and is faint/barely perceptible and within less than or equal to 10% of tumor cells (score 0) or incomplete membrane staining that is faint/barely perceptible and within > 10% of tumor cells (score 1+). Equivocal or indeterminate cases are those with circumferential membrane staining that is incomplete and or weak/moderate and within > 10% of tumor cells or complete and circumferential membrane staining that is intense and within less than or equal to 10% of tumor cells (score 2+). Pre-vaccination and post-vaccination specimens will be compared.
5. Degree of lymphocyte infiltration [ Time Frame: Up to 6 months after completion of the vaccination series timepoint ]
   Will define intra-tumoral tumor infiltration lymphocyte (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.
6. Immune cell analysis [ Time Frame: 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 allows for the imaging of formalin-fixed, paraffin embedded (FFPE) tissue sections at subcellular resolution across 20-60 distinct antigen channels. 4-6 Antibody panels that will be used include but may not be limited to an already optimized immune panel.
7. Immune infiltrates in normal tissue maximally distant from the tumor (in mastectomy samples) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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; 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

Contacts and Locations

Locations

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New York

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, United States, 10032

United States, Pennsylvania

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States, 19107

United States, Texas

M D Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elizabeth A Mittendorf; M.D. Anderson Cancer Center

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02636582
• Other Study ID Numbers: NCI-2015-02189; NCI-2015-02189 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); N01-CN-2012-00034; 2016-0164 ( Other Identifier: M D Anderson Cancer Center ); MDA2014-04-02 ( Other Identifier: DCP ); N01CN00034 ( U.S. NIH Grant/Contract ); P30CA016672 ( U.S. NIH Grant/Contract )
• First Posted: December 22, 2015
• Last Update Posted: July 2, 2021
• Last Verified: June 2021

Additional relevant MeSH terms:

Carcinoma in Situ; Carcinoma, Ductal; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Ductal, Breast; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Neoplasms, Ductal, Lobular, and Medullary; Breast Carcinoma In Situ; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Molgramostim; Vaccines; Sargramostim; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents