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History of Changes for Study: NCT02636582
Nelipepimut-S Plus GM-CSF Vaccine Therapy in Treating Patients With Breast Cancer
Latest version (submitted December 31, 2020) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 December 18, 2015 None (earliest Version on record)
2 January 11, 2016 Contacts/Locations and Study Status
3 June 20, 2016 Study Status
4 June 28, 2016 Recruitment Status, Study Status, Contacts/Locations, Eligibility and Oversight
5 July 6, 2016 Study Status
6 July 29, 2016 Recruitment Status, Study Status and Contacts/Locations
7 September 20, 2016 Study Status and Study Identification
8 November 16, 2016 Study Identification and Study Status
9 November 24, 2016 Study Status
10 December 8, 2016 Recruitment Status, Study Status and Contacts/Locations
11 December 23, 2016 Arms and Interventions, Outcome Measures, Study Description and Study Status
12 January 19, 2017 Study Status
13 January 20, 2017 Study Status
14 January 23, 2017 Study Status
15 January 24, 2017 Study Status
16 January 31, 2017 Study Status
17 April 4, 2017 Study Status and Contacts/Locations
18 April 20, 2017 Contacts/Locations, Outcome Measures, Study Identification, Eligibility, Study Design, Study Description and Study Status
19 April 28, 2017 Study Status
20 May 19, 2017 Study Status
21 May 23, 2017 Study Status
22 June 26, 2017 Study Status
23 June 30, 2017 Study Status
24 July 14, 2017 Contacts/Locations and Study Status
25 August 9, 2017 Study Status, Eligibility, Outcome Measures, Conditions and Study Description
26 August 14, 2017 Arms and Interventions and Study Status
27 August 17, 2017 Study Status
28 September 4, 2017 Arms and Interventions and Study Status
29 November 16, 2017 Study Status
30 November 24, 2017 Study Status
31 December 11, 2017 Contacts/Locations and Study Status
32 January 19, 2018 Study Status
33 February 2, 2018 Recruitment Status, Study Status and Contacts/Locations
34 February 5, 2018 Study Status
35 February 15, 2018 Outcome Measures and Study Status
36 March 2, 2018 Study Status
37 May 7, 2018 Recruitment Status, Study Status, Contacts/Locations, Eligibility, Conditions, Study Description and Study Identification
38 May 8, 2018 Outcome Measures, Arms and Interventions, Study Description and Study Status
39 May 16, 2018 Study Status
40 August 6, 2018 Study Status
41 August 14, 2018 Contacts/Locations and Study Status
42 November 20, 2018 Study Status
43 February 5, 2019 Contacts/Locations and Study Status
44 February 21, 2019 Recruitment Status, Study Status, Contacts/Locations and Oversight
45 March 6, 2019 Contacts/Locations and Study Status
46 March 11, 2019 Study Status
47 April 30, 2019 Study Status
48 July 18, 2019 Study Status and Study Design
49 September 12, 2019 Conditions and Study Status
50 October 14, 2019 Study Status
51 November 15, 2019 Study Status
52 November 18, 2019 Study Status
53 December 16, 2019 Outcome Measures, Arms and Interventions, Study Description, Study Status, Eligibility and Study Identification
54 December 20, 2019 Study Status
55 January 31, 2020 Study Status
56 February 3, 2020 Study Status
57 March 2, 2020 Study Status
58 April 14, 2020 Study Status
59 May 2, 2020 Study Status
60 June 9, 2020 Arms and Interventions and Study Status
61 June 20, 2020 Study Status
62 July 20, 2020 Study Status
63 August 4, 2020 Study Status
64 November 4, 2020 Conditions and Study Status
65 December 31, 2020 Study Status
Comparison Format:

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Study NCT02636582
Submitted Date:  July 18, 2019 (v48)

Study Identification
Unique Protocol ID: NCI-2015-02189
Brief Title: Nelipepimut-S Plus GM-CSF Vaccine Therapy in Treating Patients With Breast Cancer
Official Title: VADIS Trial: Phase II Trial of Nelipepimut-S Peptide Vaccine in Women With DCIS of the Breast
Secondary IDs: NCI-2015-02189 [Registry Identifier: CTRP (Clinical Trial Reporting Program)]
N01-CN-2012-00034
2016-0164 [M D Anderson Cancer Center]
MDA2014-04-02 [DCP]
N01CN00034 [U.S. NIH Grant/Contract]
P30CA016672 [U.S. NIH Grant/Contract]
Study Status
Record Verification: July 2019
Overall Status: Active, not recruiting
Study Start: June 14, 2016
Primary Completion: June 27, 2019 [Actual]
Study Completion:
First Submitted: December 18, 2015
First Submitted that
Met QC Criteria:
December 18, 2015
First Posted: December 22, 2015 [Estimate]
Last Update Submitted that
Met QC Criteria:
July 18, 2019
Last Update Posted: July 19, 2019 [Actual]
Sponsor/Collaborators
Sponsor: National Cancer Institute (NCI)
Responsible Party: Sponsor
Collaborators:
Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Study Description
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 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. Immune response to other tumor antigens (epitope spreading). III. Functional capacity of the immune response to vaccination. IV. Determine CTL functional capability using intracellular cytokine assays. V. Evaluate polyfunctional cytokine responses assessed by multiplex assay. VI. Presence of DCIS at resection. VII. Difference in human epidermal growth factor receptor 2 (HER2) expression in the biopsy and the surgical specimen excised post-vaccination.

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

IX. Histologic responses: Ki67 in DCIS cells (proliferation). X. Cleaved caspase 3 in DCIS cells (apoptosis). XI. 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) 2 vaccination 2 weeks apart prior to surgery.

ARM II: Patients receive sargramostim ID 2 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.

Conditions
Conditions: Ductal Breast Carcinoma In Situ
HLA-A2 Positive Cells Present
Postmenopausal
Premenopausal
Keywords:
Study Design
Study Type: Interventional
Primary Purpose: Prevention
Study Phase: Phase 2
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Single (Participant)
Allocation: Randomized
Enrollment: 13 [Actual]
Arms and Interventions
Arms Assigned Interventions
Experimental: Arm I (nelipepimut-S plus GM-CSF vaccine)
Patients receive nelipepimut-S plus GM-CSF vaccine ID 2 vaccination 2 weeks apart prior to surgery.
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 2 vaccinations 2 weeks apart prior to surgery.
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
Outcome Measures
Primary Outcome Measures:
1. Change in the number of nelipepimut-S-cytotoxic T lymphocytes (CTL), detected using a dextramer assay
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.

[Time Frame: Pre-vaccination to up to 1 month after surgery]
Secondary Outcome Measures:
2. Toxicity profile according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.03
Compared between the two groups. Adverse events by grade and relationship will be summarized by tabulation for each group.

[Time Frame: Up to 3 months after surgery]
3. Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.03
Adverse events by grade and relationship will be summarized by tabulation for each group.

[Time Frame: Up to 3 months after surgery]
4. In vivo immune response to nelipepimut-S determined by delayed type hypersensitivity reaction
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.

[Time Frame: Up to 1 months after surgery]
5. Change in the number of epitope specific-cytotoxic T lymphocyte (CTL)
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 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 of a single continuous biomarker and discrete biomarker, respectively, over time within each treatment group.

[Time Frame: Pre-vaccination to up to 6 months after surgery at the time of the final study visit]
6. Cytotoxic T lymphocyte (CTL) functional capability, measured using intracellular cytokine assays
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 of a single continuous biomarker and discrete biomarker, respectively, over time within each treatment group.

[Time Frame: Up to 6 months after completion of the vaccination series timepoint]
7. Polyfunctional cytokine responses assessed by multiplex assays
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 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 of a single continuous biomarker and discrete biomarker, respectively, over time within each treatment group.

[Time Frame: Up to 6 months after completion of the vaccination series timepoint]
8. Presence of ductal carcinoma in situ (DCIS) 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.

[Time Frame: At surgery]
9. Difference in HER2 expression 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. 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 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 of a single continuous biomarker and discrete biomarker, respectively, over time within each treatment group.

[Time Frame: Pre-vaccination to up to surgery]
10. Degree of lymphocyte infiltration
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 correlation coefficients. Paired t-test/Wilcoxon rank sum test and McNemar's test may be used to test the change of a single continuous biomarker and discrete biomarker, respectively, over time within each treatment group.

[Time Frame: Pre-vaccination to up to surgery]
11. Immune infiltration as determined by immunohistochemistry staining for CD3, CD4 and CD8
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-CSF alone-treated group, and the average difference statistic will be compared using both paired and two-sample t-tests to determine effect of the vaccine on DCIS cell proliferation. Statistically significance will be defined as a p-value less than 0.05.

[Time Frame: Pre-vaccination to up to surgery]
12. Proliferation as measured by Ki67 staining in ductal carcinoma in situ (DCIS) cells
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 calculated for the HER2 vaccine-treated group and the GM-CSF alone-treated group, and the average difference statistic will be compared using both paired and two-sample t-tests to determine effect of the vaccine on DCIS cell proliferation. Statistical significance will be defined as a p-value less than 0.05.

[Time Frame: Pre-vaccination to up to surgery]
13. Apoptosis as measured by cleaved caspase 3 in ductal carcinoma in situ (DCIS) cells
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 for the HER2 vaccine-treated group and the GM-CSF alone-treated group, and the average difference statistic will be compared using both paired and two-sample t-tests to determine effect of the vaccine on DCIS cell proliferation. Statistical significance will be defined as a p-value less than 0.05.

[Time Frame: Pre-vaccination to up to surgery]
14. Immune infiltrates in normal tissue maximally distant from the tumor (in mastectomy samples)
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 of a single continuous biomarker and discrete biomarker, respectively, over time within each treatment group. Repeated measures analysis including mixed effects model will be performed to analyze the effect of treatment on biomarkers change over time.

[Time Frame: At surgery]
Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: Female
Gender Based:
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%)
  • 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/Locations
Study Officials: Elizabeth A Mittendorf
Principal Investigator
M.D. Anderson Cancer Center
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
IPDSharing
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