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

Background: Diffuse gliomas are tumors that affect the brain and spinal cord. Gliomas that develop in people with certain gene mutations (IDH1 or IDH2) are especially aggressive. Better treatments are needed. Objective: To see if a study drug (zotiraciclib) is effective in people with recurrent diffuse gliomas who have IDH1 or IDH2 mutations. Eligibility: People aged 15 years and older with diffuse gliomas that returned after treatment. They must also have mutations in the IDH1 or IDH2 genes. Design: Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of their heart function. They will have an MRI of their brain. A new biopsy may be needed if previous results are not available. Zotiraciclib is a capsule taken by mouth with a glass of water. Participants will take the drug at home on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. They may also be given medications to prevent side effects of the study drug. The schedule for taking the study drug may vary for participants who will undergo surgery. Participants will be given a medication diary for each cycle. They will write down the date and time of each dose of the study drug. Participants will visit the clinic about once a month. They will have a physical exam, blood tests, and tests to evaluate their heart function. An MRI of the brain will be repeated every 8 weeks. Participants may remain in the study for up to 18 cycles (1.5 years).

More details:

Background: * Zotiraciclib is a multi-kinase inhibitor that has been shown to have anti-glioma effects through transcriptional suppression, mitochondrial dysfunction, and adenosine 5'-triphosphate (ATP) reduction in glioblastoma in our preclinical studies * Zotiraciclib is orally administered and likely penetrates the blood brain barrier (BBB). There has been a clinical experience in using zotiraciclib as a single agent and in combination with other chemotherapy agents in cancers, including malignant gliomas * Our phase I study of zotiraciclib and temozolomide (TMZ) in recurrent high-grade astrocytomas determined the maximum tolerated dose (MTD) of zotiraciclib in combination with TMZ and demonstrated the safety of the treatment in recurrent high-grade glioma patients * Preliminary efficacy analysis of Phase I demonstrated an improved response to zotiraciclib in combination with TMZ in IDH-mutant gliomas compared to the IDH-wildtype counterpart * A selective vulnerability to zotiraciclib as a single agent was demonstrated in the preclinical models of IDH-mutant gliomas Objectives: * Phase I: To estimate recommended phase II dose (RP2D) of zotiraciclib * Phase II: To determine 12-months progression free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with zotiraciclib in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors Eligibility: * Age \>=15; Karnofsky performance status (KPS) \>=70% * Histological confirmation of diffuse glioma, WHO grades 2-4 with IDH1/2 mutation status confirmed by DNA sequencing * Have recurrent disease * Have prior treatment of radiation and/or conventional chemotherapies * No prior use of bevacizumab as a treatment for a brain tumor Design: * This is a phase I/II study to evaluate the safety and efficacy of zotiraciclib as a single agent in recurrent IDH-mutant gliomas. * Initially, 9-24 participants (Cohort 1) will be assigned to Phase I to estimate recommended phase 2 dose (RP2D) of zotiraciclib. * Once RP2D is estimated, we will start enrollment into cohorts for Phase II, non-surgical participants (Cohorts 2-4), and surgical (Cohort 5). This trial plans to enroll up 64 evaluable participants. * Drug will be administered on days 1, 4, 8, 11, 15, 18 in cycles of 28 days for a maximum of 18 cycles. Starting dose is 200 mg. In the case that 200 mg is not tolerable, a lower dose 150 mg, will be evaluated. If 200 mg is tolerated well, a higher dose level will be evaluated at 250 mg. * Participants in the surgical cohort will get an additional single pre-treatment with one dose of study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours on Day 2 of Cycle 0. Approximately 2-4 weeks after surgery or biopsy participants in this Cohort will continue treatment with the study drug and start Day 1 of Cycle 1.

Overview

Zotiraciclib (also known as TG02, SB1317; sometimes referenced as EX 45) is an oral, multi-kinase inhibitor being developed primarily for gliomas, with additional early studies in hematologic malignancies. It has received FDA and EMA orphan drug designations for glioma. (targetedonc.com)

Mechanism of action

• Primary activity: inhibition of transcriptional CDK9, leading to decreased phosphorylation of RNA polymerase II, rapid depletion of short‑lived survival proteins (notably MCL‑1), and suppression of MYC-driven programs. Preclinical work in glioblastoma models also shows mitochondrial dysfunction, reduced glycolysis, and ATP depletion, and synergy with temozolomide. (pmc.ncbi.nlm.nih.gov)
• Kinase spectrum: inhibits multiple CDKs (1, 2, 7, 9) and has reported activity on FLT3 and JAK2; early discovery data demonstrated sub‑100 nM potency against FLT3 and CDKs with antiproliferative effects across tumor cell lines. (ashpublications.org, selleckchem.com, pubmed.ncbi.nlm.nih.gov)

Efficacy

• Recurrent high‑grade astrocytoma/glioblastoma (Phase I combination with temozolomide; NCT02942264): Among 53 patients, zotiraciclib plus temozolomide achieved a 4‑month progression‑free survival rate (PFS4) of 40% with dose‑dense temozolomide versus 25% with metronomic dosing; two partial responses were observed. IDH‑mutant gliomas had longer PFS than IDH‑wildtype (median 171 vs 74 days). (aacrjournals.org)
• Newly diagnosed elderly GBM and first‑relapse GBM (EORTC 1608 “STEAM,” Phase Ib; NCT03224104): In elderly, the maximum tolerated dose (MTD) was 150 mg twice weekly when combined with either hypofractionated radiotherapy alone or temozolomide alone. As single‑agent therapy at first relapse, PFS at 6 months was 6.7%, indicating low single‑agent activity. (pubmed.ncbi.nlm.nih.gov, ascopubs.org)

Safety

• Common and dose‑limiting toxicities across trials included neutropenia, diarrhea, elevated liver enzymes, fatigue; a grade 3 seizure was reported in combination with radiotherapy in the STEAM trial. Neutropenia with zotiraciclib can be profound but was characterized as usually transient (recovering within ~72 hours) in the Phase I combination study. (aacrjournals.org, pubmed.ncbi.nlm.nih.gov)
• Determined MTDs: 250 mg in combination with temozolomide in the recurrent high‑grade astrocytoma Phase I; 150 mg twice weekly with radiotherapy or with temozolomide in elderly newly diagnosed GBM (STEAM). (aacrjournals.org, pubmed.ncbi.nlm.nih.gov)
• Pharmacogenomics: A CYP1A2 rs2470890 variant was associated with higher zotiraciclib exposure (AUCinf) in the Phase I combination study. (aacrjournals.org)

Other clinical experience

• Early hematologic malignancy studies (Phase I) established dose levels and described gastrointestinal and hepatic adverse events, with schedules exploring daily and intermittent dosing. These were not designed to assess efficacy signals. (ascopubs.org)

Further reading

• Phase I combo with temozolomide in recurrent high‑grade astrocytoma: Clinical Cancer Research 2021 (trial NCT02942264) – randomized cohort expansion and translational analyses. https://aacrjournals.org/clincancerres/article/27/12/3298/671461/Phase-I-Study-of-Zotiraciclib-in-Combination-with (aacrjournals.org)
• EORTC 1608 “STEAM” Phase Ib in elderly newly diagnosed GBM and single‑agent at first relapse: European Journal of Cancer 2024 (NCT03224104). https://pubmed.ncbi.nlm.nih.gov/38159337/ (pubmed.ncbi.nlm.nih.gov)
• Preclinical mechanistic study in GBM demonstrating CDK9‑dependent transcriptional and metabolic effects and synergy with temozolomide: Clinical Cancer Research 2018. https://pmc.ncbi.nlm.nih.gov/articles/PMC8108069/ (pmc.ncbi.nlm.nih.gov)
• Early discovery/kinase profile: ASH Blood abstract on SB1317 (FLT3/CDK inhibition). https://ashpublications.org/blood/article/110/11/1593/56578/SB1317-a-Potent-and-Orally-Active-FLT3-CDK (ashpublications.org)
• Orphan drug designation for glioma (regulatory news summary). https://www.targetedonc.com/view/fda-grants-orphan-drug-designation-to-zotiraciclib-for-treatment-of-glioblastoma (targetedonc.com)

Notes: Zotiraciclib remains investigational; larger randomized studies would be required to clarify any benefit in combination regimens for glioblastoma. (ascopubs.org)

Last updated: Sep 2025

* 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