Tips-12 phase i clinical study of tg02 capsule in the treatment of recurrent high-grade gliomas with failed tmz treatment

Abstract BACKGROUND This study(NCT 03904628) is a dose-escalation, open-label phase I study which enrolled high grade glioma patients who failed with temozolomide(TMZ) treatment. The study purpose is to investigate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of an multi-kinase inhibitor (TG02 capsule, with primary inhibitory effects on cyclin-dependent kinases), as a new therapy for patients with recurrent high-grade glioma patients. METHODS The key inclusion criteria were 18-75 years old, glioblastoma or anaplastic astrocytoma confirmed by histology; when disease progression after receiving temozolomide; according to RANO criteria had evaluable lesions; ECOG performance status of 0-2. Eligible patients were enrolled sequentially into different dose groups and received TG02 capsule every 4 weeks .The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose(MTD). Second endpoints were pharmacokinetic characteristics and preliminary efficacy. RESULTS Between May 2019 and November 2021, twelve patients were enrolled. No DLT was occurred and MTD was not defined in study. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. Eleven patients(91.7%) had one or more treatment-related adverse events (TRAEs) assessed using CTCAE 5.0. Most frequent TRAEs were vomiting (91.7%), diarrhea (75.0%), and 50% of the patients had grade 3 or 4 AEs. There were no treatment-related deaths. The median progression-free survival (PFS) was 1.77 months (95%CI:0.82 ~ 4.24). The median OS was 9.63 months (95%CI:2.66 ~ NE). CONCLUSION TG02 capsule is safe and tolerable in patients with recurrent high-grade gliomas. Switching to using TG02 capsule showed some patients had intracranial tumor reduction who failed to treat with TMZ. TG02 can be further explored with combined therapy in the treatment of gliomas.