FDA Fast-Tracks Zotiraciclib for Recurrent High-Grade mIDH Glioma

The FDA has granted fast track designation to zotiraciclib (TG02), an oral central nervous sytem-penetrant multikinase inhibitor, for treatment of patients with recurrent high-grade gliomas (rHGG) harboring IDH1/2 mutations (mIDH).¹

This decision is supported by the completion of the phase 1 portion of an ongoing phase 1/2 trial (NCT05588141) evaluating zotiraciclib’s safety and preliminary efficacy in this patient population,² the results of which were recently presented at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting. Here, zotiraciclib exhibited tolerable safety and early clinical activity as a single agent in the safety cohort, with no dose-limiting toxicities observed and partial responses achieved by 2 patients at the 200-mg dose level.³ The 200-mg dose has been established as the recommended phase 2 dose (RP2D).

Zotiraciclib, with its potent dual mechanism of action, presents the potential for a new targeted monotherapy option that could potentially eliminate the need for cytotoxic chemotherapies. For patients with mIDH rHGG who already face the burdens of a rare cancer, including a typically poor prognosis and limited treatment options, the agent could further broaden the treatment landscape and offer improved quality of life for patients.

Building on an orphan drug designation granted to zotiraciclib for glioma in 2019,⁴ this latest designation supports an expedited development pathway to bring this option to patients with IDH mutations—who represent more than 80% of WHO grade 2 and 3 glioma cases⁵—sooner.

“Receiving FDA [f]ast [t]rack [d]esignation for zotiraciclib marks a pivotal moment in our mission to improve outcomes for patients with [mIDH] rHGG,” said Vernon Jiang, PhD, external vice president of Research and Development at Cothera Bioscience, in a news release.¹ “This designation accelerates our efforts to deliver the first breakthrough targeted therapy for this patient population since the approval of temozolomide [Temodar] in 1999.”

Overview of Zotiraciclib Research

With the conclusion of phase 1, the phase 2 portion of the supporting study is currently enrolling up to 64 patients aged 15 years and older with mIDH rHGG (WHO grades 2 to 4) who have been pretreated with radiation and/or conventional chemotherapies, excluding those previously treated with bevacizumab (Avastin). Enrollment is open for the trial’s remaining 4 cohorts: nonsurgical (cohorts 2 to 4) and surgical (cohort 5).

Investigators will assess the 12-month progression-free survival (PFS) with zotiraciclib treatment starting at the RP2D once daily for 18 28-day cycles, as well as adverse events and 5-year overall survival. The trial is estimated to complete by 2032.

Prior to the supporting study, an earlier phase 1 study (NCT02942264) evaluated the safety of zotiraciclib in combination with temozolomide for the treatment of adults with recurrent anaplastic astrocytoma (AA) and dose-dense or metronomic glioblastoma.⁶ Findings published in 2021 revealed that the combination was safe, with mostly transient neutropenia that required close monitoring.⁷ Later, the combination demonstrated early improvement in PFS in patients with IDH1 mutations, meeting the trial’s primary end point.

Both studies in the mIDH population are sponsored by the US National Institutes of Health’s National Cancer Institute. In addition to these studies, the European Organisation for Research and Treatment of Cancer assessed the efficacy and safety of zotiraciclib as a single agent and in combination with radiotherapy or temozolomide in patients with newly diagnosed AA or glioblastoma without IDH mutations in the phase 1b STEAM trial (NCT03224104).⁸

REFERENCES

1. FDA grants fast track designation to Cothera Bioscience’s zotiraciclib for treatment of recurrent high-grade glioma with IDH1/2 mutations. News release. Cothera Bioscience. November 26, 2025. Accessed December 1, 2025. https://tinyurl.com/2maybk74

2. A phase I/II study of zotiraciclib for recurrent malignant gliomas with isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations. ClinicalTrials.gov. Updated December 1, 2025. Accessed December 1, 2025. https://clinicaltrials.gov/study/NCT05588141

3. McGowan C, Li Q, Schmidt K, et al. CTNI-27. Phase I/II study of zotiraciclib for recurrent malignant gliomas with IDH mutations: results of the Phase I study. Neuro-Oncol. 2025;27(Supplement_5):v132-v132. doi:10.1093/neuonc/noaf201.0524

4. FDA grants orphan drug designation to zotiraciclib for the treatment of glioma. News release. National Cancer Institute. January 9, 2020. Accessed December 2, 2025. https://tinyurl.com/mrwbke26

5. Han S, Liu Y, Cai SJ, et al. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. Br J Cancer. 2020;122(11):1580-1589. doi:10.1038/s41416-020-0814-x

6. Zotiraciclib (TG02) plus dose-dense or metronomic temozolomide followed by randomized phase II trial of zotiraciclib (TG02) plus temozolomide versus temozolomide alone in adults with recurrent anaplastic astrocytoma and glioblastoma. ClinicalTrials.gov. Updated September 28, 2021. Accessed December 2, 2025. https://clinicaltrials.gov/study/NCT02942264

7. Wu J, Yuan Y, Long Priel DA, et al. Phase I study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas. Clin Cancer Res. 2021;27(12):3298-3306. doi:10.1158/1078-0432.CCR-20-4730

8. Le Rhun E, Gorlia T, Felsberg J, et al. Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial. Eur J Cancer. 2024;198:113475. doi:10.1016/j.ejca.2023.113475