Testing the Addition of an Anti-cancer Drug, ASTX727 (Cedazuridine, Decitabine), to Chemotherapy (Paclitaxel) and Immunotherapy (Pembrolizumab) for Metastatic Triple-Negative Breast Cancer

PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of oral decitabine and cedazuridine (ASTX727) administered concurrently with paclitaxel and pembrolizumab (MK-3475). (Part 1 \[Dose finding cohort\]) II. To further describe the adverse event profile of the combination of oral ASTX727 at the RP2D when administered concurrently with paclitaxel and pembrolizumab (MK-3475). (Part 2 \[Expansion cohort\]) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity of this combination. II. To describe the adverse event profile of the combination of oral ASTX727 administered concurrently with paclitaxel and pembrolizumab (MK-3475). (Part 1 \[Dose finding cohort\]) III. To explore the association of baseline gene expression profiles (ribonucleic acid-sequencing \[RNA-Seq\]), with focus on DNMT isoforms and TRAF-6 signaling, with clinical benefit from study treatment, as well as changes in expression after 1 cycle of treatment. (Part 2 \[Expansion cohort\]) IV. To evaluate the impact of study treatment on methylation (in tumor tissue and circulating tumor deoxyribonucleic acid \[ctDNA\]). (Part 2 \[Expansion Cohort\]) EXPLORATORY OBJECTIVES: I. To preliminarily evaluate the association of baseline DNMT3A protein expression by immunohistochemistry (IHC) and antitumor activity, as well as whether study treatment results in reduction of DNMT3A protein expression. (Part 1 \[Dose finding cohort\]) II. To preliminarily evaluate the association of baseline tumor-infiltrating lymphocytes (TILs) and PD-L1 expression with antitumor activity. (Part 1 \[Dose finding cohort\]) III. To evaluate the impact of study treatment on ctDNA methylation, peripheral blood immune phenotype and function, and serum thymidine kinase (TK1). (Part 1 \[Dose finding cohort\]) IV. To evaluate the impact of study treatment on immune phenotype (in tumor and peripheral blood) and function. (Part 2 \[Expansion cohort\]) V. To explore the impact of study treatment on immune-related genomic signaling by RNA-Seq. (Part 2 \[Expansion cohort\]) VI. To evaluate the association between baseline TILs and PD-L1 expression with treatment response, as well as changes in expression after 1 cycle of treatment. (Part 2 \[Expansion cohort\]) VII. To evaluate the association between mutations in driver genes, epigenetic genes and homologous recombination deficiency status (assessed by whole exome sequencing) with clinical outcome. (Part 2 \[Expansion cohort\]) OUTLINE: This is a dose-escalation study of ASTX727 in combination with fixed-dose pembrolizumab and fixed or reduced-dose paclitaxel, followed by a dose-expansion study. Patients receive ASTX727 orally (PO) on days 1-5, 1-4, 1-3, or days 1, 3, and 5 of each cycle, and paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 of each 28-day cycle or days 1 and 8 of each 21-day cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes every 6 weeks (treatment day varies in 28-day cycles; day 1 of every odd 21-day cycle) in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood samples and computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the trial. Patients in the dose-expansion phase also undergo a tumor biopsy during screening and day 1 of the treatment cycle 2 of the study. Patients will be followed every 6 months for 3 years post registration or until death, whichever occurs first.