Abstract OT1-01-02: Neoadjuvant pembrolizumab + decitabine followed by standard neoadjuvant chemotherapy for locally advanced HER2-breast cancer
Authors: Bear Harry Douglas , Idowu Michael O. , Poklepovic Andrew , Sima Adam , Kmieciak Maciej 
Published: March 2020

Abstract
Background: Higher levels of tumor-infiltrating lymphocytes (TIL) in breast cancers are associated with increased likelihood of pathologic complete response (pCR) to chemotherapy and improved outcomes. DNA methyltransferase inhibitors (DNMTi) can augment immune responses to cancers by upregulating tumor antigen expression, increasing MHC Class I expression and antigen presentation, decreasing numbers and activity of myeloid derived suppressor cells (MDSC) and increasing responsiveness of T lymphocytes. We have shown that decitabine augments the effectiveness of immunotherapy against murine triple negative breast cancer (TNBC).
Trial design: Patients with HER-2-negative breast cancer who are candidates for neoadjuvant chemotherapy will receive decitabine (15 mg/kg x 4 doses over 5 days) followed by 2 doses of pembrolizumab (200 mg, 2 weeks apart) prior to starting neoadjuvant chemotherapy. Two research biopsies are obtained - 1 prior to the window immunotherapy and 1 afterwards, prior to starting chemotherapy. Chemotherapy regimens: TNBC - ddAC X 4 followed by weekly Taxol + Carboplatin X 12; HR+ - ddAC X 4 followed by weekly Taxol X 12. After the safely lead-in, the sequence of regimens can be reversed, per treating physician preference.
Safety Lead-In: During immunotherapy and dose-dense AC in the first 11 patients enrolled and who have received at least 3 doses of decitabine and at least 1 dose of pembrolizumab, clinically significant immune related adverse events (irAEs) will be reported in an expedited manner. Accrual was halted until the safety lead-in phase was completed.
Brief Eligibility criteria: Primary breast cancer, candidates for neoadjuvant chemotherapy
Cohort A:
TNBC (ER&lt;10%, PR&lt;10%, Her-2 negative)
cT2, N1 or N2
cT2, 3-5 cm, N0
Any T3 or T4
Cohort B:
ER+ or PR+, Her-2 negative
cT2, N1 or N2
Any T3 or T4ECOG status 0-1
No Active autoimmune diseases
Absence of metastatic disease too extensive to consider surgery for the primary
Specific aims:
Primary endpoint:
Changes in Lymphocyte infiltration - by 10-15%
Tumor area
Stromal area
Secondary endpoints:
Gene expression (Nanostring)
Multiplex Cell Markers (DAPI/CD4/CD8/FOXP3/CK/PDL1/PDL2, and MDSCs)
pCR
Percentage of patients with lymphocyte-predominant breast cancer
Correlation of PD-L1 expression with pCR
MDSC in blood samples pre- and post- window portion
Sample Size and Statistical methods: Cohort A (TNBC) is the primary target group in this trial. When Cohort A has achieved its required sample size of 28 evaluable patients, Cohort B (HR+) will be closed to accrual irrespective of accrual to that cohort. However, in the unlikely event that accrual to Cohort B occurs at a faster rate than in Cohort A, Cohort B will be capped at 18 patients. Therefore, the projected sample size for this study is 32-50 patients. A one-sided paired t-test will be used to compare baseline and post-treatment percentage of tumor and stromal areas with infiltrating lymphocytes. The paired t-test will be applied separately to Cohorts A and B.
Present accrual and target accrual: 12 subjects have been accrued; 1 withdrew prior to any protocol therapy. The 11 patient safety lead-in has been completed. As described above, the projected total sample size is 32-50 patients.
Citation Format: Harry Douglas Bear, Michael O. Idowu, Andrew Poklepovic, Adam Sima, Maciej Kmieciak. Neoadjuvant pembrolizumab + decitabine followed by standard neoadjuvant chemotherapy for locally advanced HER2-breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-01-02.