ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas

Inclusion Criteria:

• Participants must be ≥18 years of age.

• Participants must have histologically or cytologically confirmed glioma, withdocumented IDH1 and/or IDH2 gene-mutation.

• Participants must have radiographic evidence of non-enhancing diseaseprogression/recurrence per RANO criteria for low grade gliomas (LGG).

• Patients who have received prior treatment with chemotherapy, radiation, or acombination of both are eligible. Also, patients who have not received any priortreatment 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 oftreatment.

• Participants must be on a stable or decreasing dose of glucocorticoids for 7 daysprior to registration.

• Participants must have archived primary tumor biopsies or surgical specimens foradditional exploratory translational studies. At least 100-micron length of FFPEtissue or a tissue block should be available for enrollment and for shipment to theSponsor, or a laboratory designated by the Principal Investigator. If less materialis available, participants could still be eligible after discussion with thePrincipal Investigator who will assess and confirm that there is sufficient materialfor key evaluations.

• Participants must be able to understand and willing to sign an informed consent. Alegally authorized representative may consent on behalf of a participant who isotherwise unable to provide informed consent, if acceptable to and approved by thesite 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 dueto Gilbert's disease

• Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), and alkalinephosphatase (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 glomerularfiltration rate (GFR) estimation: (140 - Age) × (weight in kg) × (0.85 iffemale)/72 × serum creatinine

• Participants must be recovered from any clinically relevant toxic effects of anyprior 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 pregnancytest within 14 days prior to the first study drug administration. Participants withreproductive potential are defined as sexually mature women who have not undergone ahysterectomy, bilateral oophorectomy or tubal occlusion or who have not beennaturally postmenopausal (i.e., who have not menstruated at all) for at least 24consecutive months (i.e., have had menses at any time in the preceding 24consecutive months). Women with reproductive potential as well as fertile men andtheir partners who are female with reproductive potential must agree to abstain fromsexual intercourse or to use 2 effective forms of contraception from the time ofgiving 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 abovecriteria 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 toregistration. One exception: participants on lomustine/CCNU must wait at least 42days 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 ≥5half-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 orwith an unexplained fever >38.5°C during screening visits or on their first day ofstudy drug administration.

• Participants with known additional malignancy that is progressing or requires activetreatment within 2 years of start of study drug. Exceptions include basal cellcarcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancerthat has undergone potentially curative therapy, or surgically treated prostatecancer.

• Participants with known hypersensitivity to any of the components of ASTX727.

• Participants with a history of myocardial infarction within the 6 months prior toscreening.

• Participants with a known history of severe and/or uncontrolled ventriculararrhythmias.

• Participants with QTc interval ≥450 msec or with other factors that significantlyincrease the risk of QT prolongation or arrhythmic events (e.g., family history oflong QT interval syndrome).

• Participants with known infection with human immunodeficiency virus (HIV) or activehepatitis B or C.

• Participants with any other medical or psychological condition, deemed by theInvestigator to be likely to interfere with a participant's ability to sign informedconsent, cooperate, or participate in the study.

• Participants with known dysphagia, short-gut syndrome, gastroparesis, or otherconditions that limit the ingestion or gastrointestinal absorption of drugsadministered orally.

• Participants with evidence of intracranial or intratumoral hemorrhage either by MRIor 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 deemedby the treating physician or surgeon not to be suitable for surgery