Zotiraciclib for Recurrent Brain Tumors with IDH Mutations

* INCLUSION CRITERIA: * Participants must have diffuse glioma, WHO grades 2-4, histologically confirmed by Laboratory of Pathology, NCI. * IDH1 or IDH2 mutation status confirmed by TruSight(TM) Oncology 500 performed in LP, NCI or prior documentation of IDH1 or IDH2 mutation status * Participants must have received prior treatment (e.g., radiation, conventional chemotherapy, or vorasidenib) prior to disease progression. * Participants must have recurrent disease, proven histologically or by imaging studies * Participants who have undergone prior surgical resection are eligible for enrollment to cohorts 1-4. * Age \>15 years * Karnofsky \>70% * Participants must have adequate organ and marrow function as defined below: * leukocytes \>=3,000/microliter * absolute neutrophil count (ANC) \>=1,500/microliter * platelets \>100,000/microliter * total bilirubin \<=2x ULN (ULN 1.3 mg/dl) except for participants with Gilbert Syndrome * AST \< 3x ULN (ULN 34U/L) * ALT \< 3x ULN (ULN 55U/L) * serum creatinine \< 1.5 mg/dL * calculated creatinine clearance by CKD-EPI equation \> 60 cc/min * Participants must have recovered from the adverse effects of prior therapy to grade 2 or less (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) * Individuals of child-bearing potential (IOCBP) and men must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, tube ligation, partner has had a previous vasectomy) at the study entry, for the duration of study treatment, and up to 3 months after the last dose of zotiraciclib * Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 3 months after study treatment discontinuation * Participants must be scheduled for brain tumor biopsy or surgical resection at NIH (Cohort 5 only) * The ability of a participant, parent or legal guardian of minor participant to understand and the willingness to sign a written informed consent document. No Legally Authorized Representative can provide initial consent. EXCLUSION CRITERIA: * More than one disease relapse in those with initial diagnosis of WHO grade 3-4, or more than two disease relapses in those with initial diagnosis of WHO grade 2 for Phase II. For Phase I enrollment, there are no limits on the number of prior recurrences. * Prior therapy with: * any investigational agent (including IDH mutant inhibitor) and/or standard of care cytotoxic therapy within 28 days prior to treatment initiation * vincristine within 14 days prior to treatment initiation * nitrosoureas within 42 days prior to treatment initiation * procarbazine within 21 days prior to treatment initiation * non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, within 7 days prior to treatment initiation * surgery within 14 days prior to treatment initiation * radiation therapy within 30 days prior to treatment initiation * bevacizumab for tumor treatment. Note: participants who received bevacizumab for symptom management, including but not limited to cerebral edema, or pseudo progression can be enrolled * Prolonged QTc \>470ms as calculated by correction formula on screening electrocardiogram (ECG) (QTCf can be used; QTCb can be used for participants with sinus bradycardia) * Prior invasive malignancies within the past 3 years prior to study treatment initiation (with the exception of non-melanoma skin cancers, carcinoma in situ of the cervix, melanoma in situ, or any localized cancer for whom the systemic standard of care therapy is not required) * History of allergic reactions attributed to compounds of similar chemical composition to zotiraciclib, such as flavopiridol * Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed at screening) * Uncontrolled intercurrent illness or social situations that would limit compliance with study requirements * Uncontrolled primary diabetes mellitus