* 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 TSO500 performed in LP, NCI or prior documentation of IDH1 or IDH2 mutation status
* Participants must have received prior treatment (e.g., radiation, conventional chemotherapy) 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 prior disease relapse (WHO grade 3-4) or more than two prior disease relapses (WHO grade 2) for Phase II only. 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
Moderate burden on patient
