Abstract PS5-07-20: Trial in progress: Phase 1 Study Targeting DNA Methyltransferases in Metastatic Triple-Negative Breast Cancer (NCI Protocol #10546)

Abstract Background: DNA methyltransferase (DNMT) isoforms 1, 3A and 3B are enzymes that regulate DNA methylation, controlling gene expression, chromatin stability and genetic imprinting. We have previously shown that DNMT3A protein expression in early triple negative breast cancer (TNBC) is associated with more aggressive clinicopathologic features (higher tumor grade, tumor proliferation and frequency of nodal metastases) and worse clinical outcomes in the absence of chemotherapy (Leon-Ferre et al, SABCS 2024). Pre-clinically, we have shown that DNMT3A protein expression predicts sensitivity to DNMT inhibitors (Yu J et al., J Clin Invest 2018), and that DNMT inhibitor treatment leads to downregulation of DNMT3A, enhanced expression of immune-related pathways, and halted tumor growth, particularly in combination with immunotherapy and paclitaxel. Methods: This is a phase 1, open-label, multicenter study evaluating the safety and recommended phase 2 dose (RP2D) of the oral DNMT inhibitor ASTX727 + paclitaxel + pembrolizumab in metastatic TNBC. ASTX727 is an oral fixed dose combination (FDC) tablet of 35 mg decitabine (active agent) and 100 mg cedazuridine (a cytidine deaminase inhibitor that prevents decitabine degradation in the bowel and liver, allowing oral delivery). The study consists of two parts: Part 1 is a dose-finding cohort, using a 3+3 design, with 5 dose levels (Table), and its primary objective is to determine the RP2D. Part 2 is an expansion cohort (n=6), with the primary objective to confirm tolerability of the regimen at the RP2D. Secondary objectives are to record the antitumor activity of the regimen, describe the AE profile, explore the association of baseline gene expression profiles with clinical benefit, and to evaluate impact of treatment on tumor and ctDNA methylation. Exploratory objectives will evaluate the association of baseline DNMT3A protein expression and antitumor activity, and the impact of treatment on the tumor and peripheral blood immune phenotype. Eligible patients are adults 18 years or older with metastatic TNBC (ER/PR ≤10%, and HER2-negative per ASCO/CAP guidelines), independent of PD-L1 expression. Patients are allowed to have received 0-3 prior lines of systemic therapy in the metastatic setting, including prior immune checkpoint inhibitors in the early and/or metastatic settings. Patients must be eligible for taxanes and have adequate organ and bone marrow function. Patients with treated brain metastases are eligible if previously treated without evidence of progression after 4 weeks. Leptomeningeal carcinomatosis is not allowed. Patients must have an ECOG performance status of ≤2 and have no gastrointestinal disorders impacting absorption of oral medications. As of June 20, 2025, the study is enrolling patients, with 10 patients dosed in the dose-finding phase. Citation Format: R. Leon-Ferre, D. M. Zahrieh, P. P. Advani, D. Quiroga, K. V. Giridhar, P. J. Dizona, D. Stover, X. Wang, A. J. Tevaarwerk, G. M. Choong, S. Yasir, K. R. Kalari, J. Foldi, R. Parajuli, M. H. Hackney, H. K. Chew, R. Wajeeha, H. Bear, E. Sharon, B. Ko, G. I. Shapiro, S. Gore, L. Pelosof, L. Wang, M. P. Goetz. Trial in progress: Phase 1 Study Targeting DNA Methyltransferases in Metastatic Triple-Negative Breast Cancer (NCI Protocol #10546) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-20.