A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

• INCLUSION CRITERIA:

• Participants must have diffuse glioma, WHO grades 2-4, histologically confirmed byLaboratory of Pathology, NCI.

• IDH1 or IDH2 mutation status confirmed by TSO500 performed in LP, NCI or priordocumentation of IDH1 or IDH2 mutation status

• Participants must have received prior treatment (e.g., radiation, conventionalchemotherapy) prior to disease progression.

• Participants must have recurrent disease, proven histologically or by imagingstudies

• Participants who have undergone prior surgical resection are eligible for enrollmentto 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 GilbertSyndrome

• 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 highlyeffective contraception (hormonal, intrauterine device (IUD), abstinence, tubeligation, partner has had a previous vasectomy) at the study entry, for the durationof study treatment, and up to 3 months after the last dose of zotiraciclib

• Breastfeeding participants must be willing to discontinue breastfeeding from studytreatment 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 tounderstand and the willingness to sign a written informed consent document. NoLegally Authorized Representative can provide initial consent.

EXCLUSION CRITERIA:

• More than one prior disease relapse (WHO grade 3-4) or more than two prior diseaserelapses (WHO grade 2) for Phase II only. For Phase I enrollment, there are nolimits on the number of prior recurrences.

• Prior therapy with:

• any investigational agent (including IDH mutant inhibitor) and/or standard ofcare 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-retinoicacid, 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 bevacizumabfor symptom management, including but not limited to cerebral edema, or pseudoprogression can be enrolled

• Prolonged QTc >470ms as calculated by correction formula on screeningelectrocardiogram (ECG) (QTCf can be used; QTCb can be used for participants withsinus bradycardia) )

• Prior invasive malignancies within the past 3 years prior to study treatmentinitiation (with the exception of non-melanoma skin cancers, carcinoma in situ ofthe cervix, melanoma in situ, or any localized cancer for whom the systemic standardof care therapy is not required)

• History of allergic reactions attributed to compounds of similar chemicalcomposition to zotiraciclib, such as flavopiridol

• Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed atscreening)

• Uncontrolled intercurrent illness or social situations that would limit compliancewith study requirements

• Uncontrolled primary diabetes mellitus