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

This phase I trial tests the safety, side effects, and best dose of ASTX727 when given in combination with a usual approach of treatment with paclitaxel and pembrolizumab in patients with triple-negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). The usual approach is defined as care most people get for this type of cancer. The usual approach for patients with metastatic triple negative breast cancer who are not in a study is chemotherapy with drugs like paclitaxel, carboplatin, cisplatin, eribulin, vinorelbine, capecitabine, gemcitabine, doxorubicin or cyclophosphamide. There is a protein called PD-L1 that helps regulate the body's immune system. For patients who have PD-L1+ tumors, immunotherapy (pembrolizumab) is usually added to paclitaxel or carboplatin/gemcitabine as initial treatment. For patients who have PD-L1-negative tumors, chemotherapy alone is used, without immunotherapy. ASTX727 is a combination of two drugs, decitabine and cedazuridine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ASTX727 with usual treatment approach with paclitaxel and pembrolizumab may be able to shrink or stabilize the tumor for longer than the usual approach alone in patients with 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.