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

This is a single center, phase I/Ib clinical trial evaluating the combination of the poly adenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib with the DNA methyltransferase (DNMT) inhibitor ASTX727, which is an oral formulation of decitabine with cedazuridine (a cytidine deaminase inhibitor that allows for oral administration). The study population consists of adults with advanced/metastatic solid tumor malignancies with germline or somatic mutations in the HRR pathway (i.e., BReast CAncer gene 1 (BRCA1), BReast CAncer gene 2(BRCA2), Partner And Localizer of BRCA2 (PALB2), ATM, and/or Checkpoint kinase 2 (CHEK2) mutations).

Inclusion Criteria: 1. Participants must have histologically or cytologically confirmed advanced solid tumors (any solid tumor type) with: Phase I, Dose Escalation: Germline and/or somatic mutation\* in one or more of the following genes: BRCA1, BRCA2, PALB2, ATM, and/or CHEK2. Phase Ib, Dose Expansion\*\*: 1. Expansion Cohort A (n=6): Germline mutation\* (with or without accompanying somatic mutation) in one or more of the following genes: BRCA1, BRCA2, PALB2, ATM, and/or CHEK2; 2. Expansion Cohort B (n=6): Germline and/or somatic mutation\* in one or more of the following genes: BRCA1, BRCA2, PALB2, ATM, and/or CHEK2. * Testing for DNA repair mutations should occur prior to study consent or enrollment via a CLIA-approved test. 2. Has measurable disease per RECIST 1.1 as assessed by the investigator. Lesions situated in previously irradiated areas are considered measurable if progression has been demonstrated in such lesions. 3. Participants may have received any lines of prior therapy and is refractory or intolerant to therapy approved for their condition or unwilling to receive currently approved therapy. 4. Prior PARP inhibitors are allowed, provided the following two criteria are met: 1. Participant has NOT required toxicity related dose reductions or dose delays during prior PARP inhibitor treatment; and 2. Participant has NOT experienced any allergic reaction to PARP inhibitors. 5. Age \>=18 years 6. Eastern Cooperative Oncology Group (ECOG) performance status \60% 7. Demonstrates adequate organ function as defined below: Adequate bone marrow function: 1. hemoglobin \>=10.0 g/dl 2. absolute neutrophil count \>=1,500/microliter (mcL) 3. platelets \>=100,000/mcL Adequate hepatic function: 1. total bilirubin ≤ 1.5 x institutional upper limit normal (ULN) 2. aspartate aminotransferase (AST)/(SGOT) \