Inclusion Criteria:
* Participants must be ≥18 years of age.
* Participants must have histologically or cytologically confirmed glioma, with documented IDH1 and/or IDH2 gene-mutation.
* Participants must have radiographic evidence of non-enhancing disease progression/recurrence per RANO criteria for low grade gliomas (LGG).
* Patients who have received prior treatment with chemotherapy, radiation, or a combination of both are eligible. Also, patients who have not received any prior treatment for their glioma are also eligible.
* Participants must be ≥12 weeks from completion of radiation.
* Participants must have a baseline brain MRI scan within 28 days prior to Day 1 of treatment.
* Participants must be on a stable or decreasing dose of glucocorticoids for 7 days prior to registration.
* Participants must have archived primary tumor biopsies or surgical specimens for additional exploratory translational studies. At least 100-micron length of FFPE tissue or a tissue block should be available for enrollment and for shipment to the Sponsor, or a laboratory designated by the Principal Investigator. If less material is available, participants could still be eligible after discussion with the Principal Investigator who will assess and confirm that there is sufficient material for key evaluations.
* Participants must be able to understand and willing to sign an informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
* Participants must have KPS ≥ to 70
* Participants must have expected survival of ≥ 6 months.
* Participants must have adequate bone marrow function as evidenced by:
* Leukocytes ≥ 3,000/mcL
* Absolute neutrophil count ≥1500/mcL;
* Hemoglobin ≥10 g/dL
* Platelets ≥100,000/mcL
* Participants must have adequate hepatic function as evidenced by:
* Serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease
* Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 x ULN.
* Participants must have adequate renal function as evidenced by:
* Serum creatinine ≤2.0 x ULN
* OR Creatinine clearance \>40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine
* Participants must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Participants with residual Grade 1 toxicity due to prior chemotherapy are allowed).
* Female participants with reproductive potential must have a negative serum pregnancy test within 14 days prior to the first study drug administration. Participants with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., have had menses at any time in the preceding 24 consecutive months). Women with reproductive potential as well as fertile men and their partners who are female with reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 90 days (females and males) following the last dose of ASTX727.
* Participants enrolling in the expansion cohort (Arm B) must meet all of the above criteria and must have surgically accessible tumors and be surgical candidates.
Exclusion Criteria:
* Participants with enhancing disease on brain MRI.
* Participants who received systemic anticancer therapy \<28 days prior to registration. One exception: participants on lomustine/CCNU must wait at least 42 days from last date of drug administration to registration.
* Participants who received an investigational agent \<14 days prior to registration. In addition, the first dose of ASTX727 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
* Participants with prior treatment with bevacizumab (Avastin) are excluded.
* Participants who are pregnant or breast-feeding.
* Participants with an active severe infection that requires anti-infective therapy or with an unexplained fever \>38.5°C during screening visits or on their first day of study drug administration.
* Participants with known additional malignancy that is progressing or requires active treatment within 2 years of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, or surgically treated prostate cancer.
* Participants with known hypersensitivity to any of the components of ASTX727.
* Participants with a history of myocardial infarction within the 6 months prior to screening.
* Participants with a known history of severe and/or uncontrolled ventricular arrhythmias.
* Participants with QTc interval ≥450 msec or with other factors that significantly increase the risk of QT prolongation or arrhythmic events (e.g., family history of long QT interval syndrome).
* Participants with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
* Participants with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a participant's ability to sign informed consent, cooperate, or participate in the study.
* Participants with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
* Participants with evidence of intracranial or intratumoral hemorrhage either by MRI or CT scan. Participants with resolving post-surgical changes, punctate/micro-hemorrhage, or hemosiderin are eligible.
* Participants enrolling in the expansion cohort will be excluded is they are deemed by the treating physician or surgeon not to be suitable for surgery
