Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) and entinostat in combination in patients with advanced and refractory solid tumors based on dose limiting toxicities (DLTs) of the combination of ZEN003694 and entinostat. (Phase I) II. To determine the overall response rate (ORR) of ZEN003694 and entinostat in advanced/progressive pancreatic cancer. (Phase II) SECONDARY OBJECTIVES: I. To describe the safety profile of ZEN003694 and entinostat in advanced and refractory solid tumors. (Phase I) II. To determine the progression-free survival (PFS), duration of response (DOR), and overall survival (OS) of ZEN003694 and entinostat in this patient population. (Phase I) III. To describe the safety profile of ZEN003694 and entinostat in advanced/progressive pancreatic cancer. (Phase II) IV. To determine the progression-free survival (PFS), duration of response (DOR), and overall survival (OS) of ZEN003694 and entinostat in this patient population. (Phase II) V. To assess the effect of ZEN003694 and entinostat therapy on apoptosis, as measured by an apoptosis multiplex immunoassay. (Phase I Daily Dosing of ZEN003694) EXPLORATORY OBJECTIVES: I. To assess the effect of ZEN003694 and entinostat therapy on c-MYC and YAP1 as measured by apoptosis immunofluorescence assay. (Phase I Daily Dosing of ZEN003694) II. To assess the effect of ZEN003694 and entinostat therapy on c-MYC and YAP1 as measured by ribonucleic acid (RNA) and protein expression. (Phase I Daily Dosing of ZEN003694) III. To assess the effect of ZEN003694 and entinostat therapy on tumor burden and gene expression patterns as measured by RNA sequencing (RNASeq) on circulating tumor deoxyribonucleic acid (DNA) (ctDNA) specimens. (Phase I Daily Dosing of ZEN003694) OUTLINE: This is a phase I, dose-escalation study of ZEN003694 in combination with entinostat followed by a phase II study. PHASE I RUN-IN PERIOD (DAILY DOSING) (NO LONGER USED PER AMENDMENT DATED JUNE 12, 2025): Patients receive ZEN003694 orally (PO) once daily (QD) during days -14 to 1. Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE I \& II COMBINATION TREATMENT (DAILY DOSING) (NO LONGER USED PER AMENDMENT DATED JUNE 12, 2025): Patients receive entinostat PO QW on days 1, 8, 15, and 22, and ZEN003694 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo core needle biopsy on day 1 of cycle 1, and on day 1 of cycle 14. PHASE I and PHASE II (INTERMITTENT DOSING): Patients receive entinostat PO on days 1, 8, 15, and 22 of each cycle and ZEN003694 PO QD on days 1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT) throughout the study. After completion of study treatment, patients are followed for 30 days.