Olaparib and ASTX727 in BRCA1/2- and Homologous Recombination Deficient (HRD)-Mutated Tumors

PRIMARY OBJECTIVES: I. To assess the safety and tolerability of olaparib and ASTX7272 in patients with advanced solid tumors and germline or somatic mutations in the homologous recombination repair (HRR) pathway. II. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for olaparib and ASTX7272 in patients with advanced solid tumors and germline or somatic mutations in the HRR pathway. SECONDARY OBJECTIVES: I. To evaluate the preliminary efficacy of the recommended dose level of olaparib and ASTX727 in patients with solid tumor malignancies and germline or somatic mutations in the HRR pathway. EXPLORATORY OBJECTIVES: I. To characterize HRD mutations in tumor samples and assess functional impact on HRR. II. To assess cell free deoxyribonucleic acid (cfDNA) as a predictive biomarker of response and resistance. III. To create patient-derived xenograft (PDX) and patient-derived organoid (PDO) models for sensitive and resistant tumors from patients treated with olaparib and ASTX727. OUTLINE: Testing for DNA repair mutations should occur prior to study consent or prior to enrollment via a Clinical Laboratory Improvement Amendments of 1988 (CLIA)-approved test. This study uses a 3+3 design. In phase 1, participants will be assigned to the starting dose. If no DLTs are found in the first cycle for the first 3 participants, an additional cohort at the next dose level will open for enrollment. In phase 1b, participants will receive the recommended phase 2 dose (RP2D). Participants will be followed for approximately 30 days after discontinuation of study treatment for safety, and every 16 weeks for up to 2 years.