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Exemestane

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Nine days prior to their scheduled surgery, entinostat 5mg PO given once weekly on day 1 and day 8

oral drug, 5mg tablet given once weekly x 2 doses

Lisa Carey, MD

This study is investigational and is not designed to treat cancer. In other words, the study drug, entinostat, is not being given to treat cancer. Instead, the study team is looking at the effects of entinostat on tumor tissue for research purposes only.

Approximately 246,660 cases of breast cancer were diagnosed in the United States in 2016. Its detection and treatment remains a major concern in women's healthcare. In particular, TNBC accounts for approximately 15-20% of all breast cancers. Research into treatment for breast cancer relies more and more on understanding how the cancer cells act when they are exposed to an anti-cancer drug. How most cancer cells act when exposed to anti-cancer drugs and which patients as a result may benefit the most from these drugs is not well known. Additional studies are required to determine the cells' reactions. The purpose of part 1 of this study is to better understand how TNBC tumors react to one particular cancer drug, entinostat. Entinostat is currently being studied across multiple clinical trials for the treatment of breast cancer, other solid tumors and blood cancers. Entinostat is investigational and has not yet been FDA approved for the treatment of cancer.

Studies have shown that a good way to determine how cancer acts when exposed to anti-cancer drugs is a short-term preoperative window study. In this type of study, subjects receive a study drug a couple of days before surgery. Leftover tissue from surgery is then used to determine some of the effects that a study drug may have on the tumor. In this study, subjects will receive two doses of entinostat prior to undergoing planned surgery. Leftover tissue from this surgery will then be used to determine the effects entinostat has on tumor cells. For example, the study team will examine if the types of genes and proteins that the tumor expresses as a result of entinostat exposure increases or decreases the likelihood that the tumor will not continue to grow. A gene is a unit of DNA. Genes make up the chemical structure carrying your genetic information that may determine human characteristics (i.e., eye color, height and sex). This study will focus on discovering how entinostat affects a wide variety of genes in tumor cells.

Primary Objective and Endpoint To identify decrease in Ki-67 mRNA following treatment with entinostat across TNBC breast cancers.

Secondary Objectives and Endpoints To identify messenger ribonucleic acid (mRNA) gene expression changes following treatment with entinostat, across TNBC.

To evaluate changes in the proliferation signature by mRNA expression following treatment with entinostat across TNBC.

To identify differential kinome activation before and after treatment with entinostat across TNBC

To correlate mutation and/or copy number variations by whole exome sequencing (WES) with mRNA gene expression changes and reduction of proliferation signature following treatment with entinostat across TNBC.

To correlate protein lysine hyperacetylation in peripheral blood and tumor from pre- and post-entinostat treated TNBCs.

To explore molecular subtype, Programmed death-ligand 1 (PD-L1) and other immune checkpoint molecule expression, immune gene and innate anti-programed cell death-1 resistance (IPRES) expression signatures and phenotypes of tumor-infiltrating lymphocytes, including delineation of effector and regulatory T cells, and define T cell receptor (TCR) repertoire prior to and following entinostat treatment in TNBCs. We will also explore mutation and copy number variation status, and predicted major histocompatibility complex (MHC) class I neoantigen burden.

To document safety of entinostat in patients with TNBC prior to their scheduled surgical resection per National Cancer Institute - Common Terminology for Adverse Events (NCI-CTCAE v4.0).

Window of Opportunity Trial of Entinostat in Patients With Newly Diagnosed Stage I-IIIC,TNBC

A Non-randomized, Non-comparative, Open-label, Window Trial of Entinostat Given With or Without Exemestane in Patients With Newly Diagnosed, Stage I-IIIC, Hormone Receptor - Positive (HR+) or Triple Negative Breast Cancer (TNBC)

RNA will be extracted from tumor samples using the Qiagen RNEasy Mini RNA extraction kit. mRNA-Seq libraries will made according to the Illumina TruSeq RNA Access protocol. Determination of molecular subtypes and relative expression of genes (i.e. Ki-67 as primary objective) and gene signatures from mRNA-seq data will be done. Change (decrease) in Ki-67 mRNA expression from will be measured by log2 fold-change in Ki-67 mRNA-seq expression from pre-treatment to post-treatment within each patient.

RNA will be extracted from tumor samples using the Qiagen RNEasy Mini RNA extraction kit. mRNA-Seq libraries will made according to the Illumina TruSeq RNA Access protocol. Determination of molecular subtypes and relative expression of genes (i.e. Ki-67 as primary objective) and gene signatures from mRNA-seq data will be done. Expression of mRNA-seq will be measured in terms of relative standard error of the mean (RSEM) expected read counts after normalization by upper quartile normalization to adjust for between-sample differences in library sizes.

RNA will be extracted from tumor samples using the Qiagen RNEasy Mini RNA extraction kit. mRNA-Seq libraries will made according to the Illumina TruSeq RNA Access protocol. Determination of molecular subtypes and relative expression of genes (i.e. Ki-67 as primary objective) and gene signatures from mRNA-seq data will be done. Genes belonging to the proliferation signature will be individually examined and summarized by descriptive statistics.

Tissue samples for pre-treatment kinome analysis will be obtained from tissue remaining from the diagnostic, pre-treatment baseline biopsy (or from additional core needle biopsy of accessible tissue at study entry, if insufficient tissue is available from the diagnostic biopsy). Tissue samples for post-treatment kinome analysis will be obtained from the surgical procedure. A chemical proteomics approach will be employed to define the activity of a significant percentage of the expressed kinome in cells and tumors. Differential kinome activation will be measured in terms of the log2 fold change in MaxQuant Label Free Quantification (LFQ) intensity before and after treatment.

The T-cell receptor (TCR) repertoires of tumors and matched peripheral blood samples pre and post treatment with entinostat will be profiled, as well as the presence of dominant tumor-infiltrating clonotypes in the peripheral blood. RNA and whole-exome sequencing on tumor samples will be performed to capture molecular subtype, PD-L1 and other immune checkpoint molecule expression, immune gene signature and IPRES expression (ie, IPRES is a transcriptional signature associated with innate anti-PD-1 resistance) mutation and copy number variation status, and predicted MHC class I neoantigen burden. Continuous variables such as mRNA expression and DNA copy number will be assessed via Spearman Correlation, and correlation between categorical variables such as mutations and T-cell Phenotype will be assessed via Fisher's Exact Test.

Changes in protein lysine acetylation in blood mononuclear cells (PBMCs) will be assessed using an assay developed by the Trepel Laboratory, NCI/NIH. Pre to post-treatment change in protein lysine acetylation.will be measured in terms of the log2 fold change in MaxQuant LFQ intensity before and after treatment, and will be summarized with descriptive statistics

Any patient who receives at least one dose of entinostat on this protocol will be evaluable for toxicity, with toxicity evaluated using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.

Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events (SAEs) that are considered related to entinostat, all events of death, and any study specific issue of concern.

Spots Global Cancer Trial Database for er positive pr positive breast cancer