SYST-02 PHASE ⅡB CLINICAL TRIAL OF NEOADJUVANT CHEMOTHERAPY REVERSING GLIOMA STEM CELLS CHEMORESISTANCE IN NEWLY DIAGNOSED GBM WITH MGMT PROMOTER UNMETHYLATION

PURPOSE: To evaluate clinical efficacy and safety of combination of nicardipine and valproic acid on temozolomide (TMZ) neoadjuvant chemotherapy targeting on glioma stem cells (GSCs) in newly diagnosed glioblastoma multiforme (GBM) patients with O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylation. METHODS: From June 2018 to April 2021, newly diagnosed GBM patients after tumor surgical removal and concurrent radio-chemotherapy with TMZ, with MGMT promoter unmethylation were randomly assigned to two groups. The control group was applied standard TMZ regimen. The trial group was administered standard TMZ regimen, plus nicardipine(20mg/d) and valproic acid (1.2g/d) as neoadjuvant treatment against GSCs chemoresistance. The relevant treatment data and adverse reactions of the patients were collected, Karnofsky performance status (KPS) score, progression-free survival (PFS) and overall survival (OS) were evaluated during patient follow-up. RESULTS: 33 patients were enrolled in this study, eighteen patients were randomly assigned in the trial group and 15 patients were in the control group. There was no statistical difference in gender composition, age, degree of surgical resection, or KPS score before treatment between the two groups. The median progression-free survival (mPFS) in the trial group was 10.8 months (95%CI 5.81-15.79 month), and the mPFS in the control group was 7.1 months (95%CI 5.12-9.08 month), which was a statistically difference (Log-Rank test P=0.033). The median overall survival (mOS) increased from 12.1 months (95%CI 9.18-15.00 month) in the control group to 15.7 months (95%CI 7.67-23.73 month) in the trial group (Log-Rank test P=0.015). There was no statistically significant difference in the incidence of adverse reactions between the two groups, and there were no treatment regimen related deaths. CONCLUSIONS: TMZ combined with neoadjuvant of nicardipine and valproic acid against GSCs chemoresistance can prolong the survival time of patients who was newly diagnosed glioblastoma with MGMT promoter unmethylation. The preferred regimen can be applied safely without serious adverse events, which deserved further multi-center clinical investigations.