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

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02636582
First received: December 18, 2015
Last updated: June 26, 2017
Last verified: May 2017
  Purpose
This randomized 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 Intervention Phase
Ductal Breast Carcinoma In Situ Other: Laboratory Biomarker Analysis Drug: Nelipepimut-S Plus GM-CSF Vaccine Biological: Sargramostim Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant
Primary Purpose: Prevention
Official Title: VADIS Trial: Phase II Trial of Nelipeimut-S Peptide Vaccine in Women With DCIS of the Breast

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 ch


Secondary Outcome Measures:
  • Apoptosis as measured by cleaved caspase 3 in DCIS cells [ Time Frame: Pre-vaccination to up to surgery ]
    The % positive cells in the DCIS samples from pre-treatment and post-treatment samples and a "difference statistic" for each participant will be calculated (the change in % positive between pre- and post-treatment sample for each participant). If the distribution of % positive values is not a normal distribution, then it may be necessary to log-transform the primary data before calculating the difference statistic. These biomarker data will be visualized by plotting each participant's pre- and post-treatment value ("spaghetti plots"). The average "difference statistic" will then be calculated

  • Change in the number of epitope specific-CTL [ Time Frame: Pre-vaccination to up to 3 months after surgery at the time of the final study visit ]
    Evidence of inter-antigenic epitope spreading will be evaluated by quantifying the number of CTL specific for the folate binding protein derived epitope E39 (EIWTHSYKV) and the cyclin E-derived epitope CCNE144-152 (ILLDWLMEV). The association among various continuous and discrete biomarkers or treatment groups will be assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot and trellis plot, etc., and may be tested by t-test/analysis of variance (ANOVA)/Wilcoxon rank sun test/Kruskal-Wallis test, when appropriate. Correlation between continuous biomarkers will

  • CTL functional capability, measured using intracellular cytokine assays [ Time Frame: Up to 3 months after completion of the vaccination series timepoint ]
    The association among various continuous and discrete biomarkers or treatment groups will be assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot and trellis plot, etc., and may be tested by t-test/ANOVA/Wilcoxon rank sun test/Kruskal-Wallis test, when appropriate. Correlation between continuous biomarkers will be examined by Pearson or Spearman rank correlation coefficients. The association between discrete biomarkers will be tested by chi-square or Fisher's exact test. Paired t-test/Wilcoxon rank sum test and McNemar's test may be used to test the change

  • Degree of lymphocyte infiltration [ Time Frame: Pre-vaccination to up to surgery ]
    Intra-tumoral and stromal tumor infiltrating lymphocytes 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. The association among various continuous and discrete biomarkers or treatment groups will be assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot and trellis plot, etc., and may be tested by t-test/ANOVA/Wilcoxon rank sun test/Kruskal-Wallis test, when appropriate. Correlation between continuous biomarkers will be examined by Pearson or Spearman rank

  • Difference in HER2 expression in the biopsy and the surgical specimen excised post-vaccination [ Time Frame: Pre-vaccination to up to surgery ]
    HER2 scoring will be determined according to the American Society of Clinical Oncology/College of American Pathologists clinical guidelines. Pre-vaccination and post-vaccination specimens will be compared. The association among various continuous and discrete biomarkers or treatment groups will be assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot and trellis plot, etc., and may be tested by t-test/ANOVA/Wilcoxon rank sun test/Kruskal-Wallis test, when appropriate. Correlation between continuous biomarkers will be examined by Pearson or Spearman rank corr

  • Immune infiltrates in normal tissue maximally distant from the tumor (in mastectomy samples) [ Time Frame: At surgery ]
    The association among various continuous and discrete biomarkers or treatment groups will be assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot and trellis plot, etc., and may be tested by t-test/ANOVA/Wilcoxon rank sun test/Kruskal-Wallis test, when appropriate. Correlation between continuous biomarkers will be examined by Pearson or Spearman rank correlation coefficients. The association between discrete biomarkers will be tested by chi-square or Fisher's exact test. Paired t-test/Wilcoxon rank sum test and McNemar's test may be used to test the change

  • Immune infiltration as determined by immunohistochemistry staining for CD3, CD4 and CD8 [ Time Frame: Pre-vaccination to up to surgery ]
    Total number of positive cells for each immune cell marker in 10 high power fields in the DCIS samples from pre-treatment and post-treatment samples will be counted and a "difference statistic" for each participant will be calculated (the change in the total number of marker-positive infiltrating immune cells in the pre- and post-treatment samples for each participant). These biomarker data will be visualized by plotting each participant's pre- and post-treatment value ("spaghetti plots"). The average "difference statistic" will then be calculated for the HER2 vaccine-treated group and the GM-

  • In vivo immune response to nelipepimut-S determined by delayed type hypersensitivity reaction [ Time Frame: Up to 1 months after surgery ]
    For each patient, pre- and post-vaccination delayed type hypersensitivity (DTH) measurements will be compared. DTH data will be presented as means +/- standard errors and compared (pre- versus [vs] post-vaccination) using a student t test.

  • Incidence of adverse events, graded according to NCI CTCAE 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.

  • Polyfunctional cytokine responses assessed by multiplex assays [ Time Frame: Up to 3 months after completion of the vaccination series timepoint ]
    A standard curve will be generated for each cytokine and the cytokine concentration in individual patient samples will be determined by comparison to that standard curve. The association among various continuous and discrete biomarkers or treatment groups will be assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot and trellis plot, etc., and may be tested by t-test/ANOVA/Wilcoxon rank sun test/Kruskal-Wallis test, when appropriate. Correlation between continuous biomarkers will be examined by Pearson or Spearman rank correlation coefficients. The associati

  • Presence of ductal carcinoma in situ (DCIS) at resection [ Time Frame: At surgery ]
    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.

  • Proliferation as measured by Ki67 staining in DCIS cells [ Time Frame: Pre-vaccination to up to surgery ]
    The % Ki67-positive cells in the DCIS samples from pre-treatment and post-treatment samples and a "difference statistic" for each participant will be calculated (the change in % Ki67 between pre- and post-treatment sample for each participant). If the distribution of % Ki67 values is not a normal distribution, then it may be necessary to log-transform the primary % Ki67 data before calculating the difference statistic. These biomarker data will be visualized by plotting each participant's pre- and post-treatment value ("spaghetti plots"). The average "difference statistic" will then be calcula

  • 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.


Estimated Enrollment: 108
Actual Study Start Date: June 14, 2016
Estimated Primary Completion Date: March 14, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (nelipepimut-S plus GM-CSF vaccine)
Patients receive nelipepimut-S plus GM-CSF vaccine ID 3 vaccination 2 weeks apart prior to surgery.
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
Experimental: Arm II (sargramostim)
Patients receive sargramostim ID 3 vaccinations 2 weeks apart prior to surgery.
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

Detailed Description:

PRIMARY OBJECTIVES:

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.

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. In vivo immune response to nelipepimut-S determined by delayed type hypersensitivity reaction; III. Immune response to other tumor antigens (epitope spreading). IV. Functional capacity of the immune response to vaccination. V. Determine CTL functional capability using intracellular cytokine assays. VI. Evaluate polyfunctional cytokine responses assessed by multiplex assay. VII. Presence of DCIS at resection. VIII. Difference in human epidermal growth factor receptor 2 (HER2) expression in the biopsy and the surgical specimen excised post-vaccination.

IX. Histologic responses: degree of lymphocyte infiltration determined on hematoxylin and eosin (H&E) stained slides and by immunohistochemistry staining for CD3, CD4 and CD8.

X. Histologic responses: proliferation-related Ki-67 antigen (Ki67) in DCIS cells (proliferation).

XI. Histologic responses: cleaved caspase 3 in DCIS cells (apoptosis). XII. Immune infiltrates in normal tissue maximally distant from the tumor (in mastectomy samples).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nelipepimut-S plus GM-CSF vaccine intradermally (ID) 3 vaccination 2 weeks apart prior to surgery.

ARM II: Patients receive sargramostim ID 3 vaccinations 2 weeks apart prior to surgery, and 3 vaccinations 1 months apart post-surgery.

After completion of study treatment, patients are followed up at 1 and 3 months.

  Eligibility

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

Inclusion Criteria:

  • Participants must have a diagnosis of DCIS made by core needle biopsy
  • Participants must have an area of radiographic abnormality measuring at least 1 cm
  • Participants must be human leukocyte antigen (HLA)-A2 positive
  • Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,500/mm^3
  • 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:

  • Bilateral breast malignancy or an unconfirmed, nonmalignant but suspicious mass in the opposite breast to include atypical ductal hyperplasia
  • Invasive breast cancer
  • History of prior breast cancer
  • History of prior ductal carcinoma in situ (DCIS); 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; women of child-bearing potential 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 steroids
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02636582

Locations
United States, Massachusetts
Dana-Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Judy E. Garber    617-632-5770    Judy_Garber@dfci.harvard.edu   
Principal Investigator: Judy E. Garber         
United States, New York
Columbia University/Herbert Irving Cancer Center Recruiting
New York, New York, United States, 10032
Contact: Katherine D. Crew    212-305-1732    kd59@columbia.edu   
Principal Investigator: Katherine D. Crew         
United States, Pennsylvania
Thomas Jefferson University Hospital Not yet recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Adam C. Berger    215-955-1622    Adam.Berger@jefferson.edu   
Principal Investigator: Adam C. Berger         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Elizabeth A. Mittendorf    713-792-2362    eamitten@mdanderson.org   
Principal Investigator: Elizabeth A. Mittendorf         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Elizabeth Mittendorf M.D. Anderson Cancer Center
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02636582     History of Changes
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 ( US NIH Grant/Contract Award Number )
P30CA016672 ( US NIH Grant/Contract Award Number )
Study First Received: December 18, 2015
Last Updated: June 26, 2017

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma in Situ
Carcinoma, Ductal, Breast
Carcinoma, Intraductal, Noninfiltrating
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Carcinoma, Ductal
Adenocarcinoma
Neoplasms, Ductal, Lobular, and Medullary
Vaccines
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 28, 2017