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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: VADIS Trial: Phase II Trial of Nelipeimut-S Peptide Vaccine in Women With DCIS of the Breast

Brief Summary: 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.

Detailed Summary:

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.

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



Original Primary Outcome: 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 completion of the vaccination series timepoint ]

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


Current Secondary Outcome:

  • 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 immun

    Original Secondary Outcome:

    • Apoptosis as measured by cleaved caspase 3 in DCIS cells [ Time Frame: Up to 9 months after completion of the vaccination series timepoint ]
      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 9 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 9 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: Up to 9 months after completion of the vaccination series timepoint ]
      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 9 months after completion of the vaccination series timepoint ]
      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: Up to 9 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
    • Immune infiltration as determined by immunohistochemistry staining for CD3, CD4 and CD8 [ Time Frame: Up to 9 months after completion of the vaccination series timepoint ]
      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-

      Information By: National Cancer Institute (NCI)

      Dates:
      Date Received: December 18, 2015
      Date Started: June 2016
      Date Completion:
      Last Updated: April 28, 2017
      Last Verified: April 2017