Discovering novel therapies for glioma patients

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Based on our previous preclinical and clinical works in high-grade malignant gliomas, FDA granted the orphan drug designation for ZTR in malignant gliomas treatment. Based on the observations from the previous clinical study, we continued to investigate the selective effect of ZTR in a subset of gliomas. This ongoing project includes both preclinical and clinical studies of ZTR in IDH-mutant gliomas. In the preclinical studies, we tested the responses to ZTR in both IDH mutant and wildtype glioma models. We demonstrated the increased sensitivity to ZTR in IDH-mutant gliomas compared to the IDH-wildtype tumor. A lower IC50 in IDH-mutant cells compared to the IDH-wildtype glioma cells was demonstrated in patient-derived GSC lines and isogenic mouse cells with and without IDH mutation. A lower dose of ZTR was able to suppress transcription through inhibition of cyclin-dependent kinase 9 (CDK9) and RNAPOL II in mutant cells but not in wild-type cells. Apoptosis, mitochondrial dysfunction and ATP reduction are also seen in low dose ZTR-treated IDH-mutant gliomas but not in IDH wildtype tumors. A significant survival benefit of single-agent ZTR is observed in mouse model of IDH-mutant but not wild-type gliomas. Based on the preclinical findings, we hypothesized that IDH-mutant glioma has increased sensitivity to ZTR due to its unique tumor biology. Single-agent ZTR in patients with IDH-mutant gliomas will improve clinical outcomes, including survival benefits and less of toxicities. To test the hypothesis in the clinical trial setting, I have designed a clinical trial in IDH-mutant glioma patients. Entitled "A Phase I/II Study of Zotiraciclib for Recurrent High-Grade Gliomas with Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations". In Phase I part, the primary objective is to estimate recommended phase II dose (RP2D) of ZOT. In Phase II, the primary objective is to determine 12-month progression-free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with ZTR in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors. In the phase II part, we built a surgical cohort. Participants in the surgical cohort will get an additional single pre-treatment with one dose of the study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours. The surgical sample will be used for PK and PD analysis to determine the drug exposure and biological effect of the study drug in the tumor. More importantly, we plan to longitudinally evaluate Participant Reported Outcomes (PRO)s measures using self-reported symptom severity and interference with daily activities using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) or the M.D. Anderson Symptom Inventory-Spine Module (MDASI-SP) instrument. This will evaluate the symptom burdens and quality of life while patients receiving the treatment for tumor control. Lastly, the pharmacogenetic (PG) features of participants receiving ZTR will be determined and correlate with treatment response and toxicities. The results of this Phase 1 study have been completed and published.