Abstract: Background and purpose: There is no standard treatment for recurrent high-grade gliomas. This study aimed to evaluate the curative efficacy and safety of bevacizumab plus nitrosoureas regimen in patients with recurrent high-grade gliomas, and to explore the molecular biomarkers for efficacy prediction. Methods: This was a single-arm phase Ⅱ clinical trial (Number NCT02698280) enrolling patients with recurrent high-grade gliomas. Every 6 weeks was defined as one therapeutic cycle. Bevacizumab was administered intravenously at 5 mg/kg every 3 weeks; and nitrosoureas at 90 mg/m² every 6 weeks. Radiological response was assessed every 6 weeks according to the Response Assessment in Neuro-Oncology (RANO) criteria. The primary endpoint was progression-free survival (PFS), progression-free survival at 6 months (PFS-6) and radiological response. The secondary endpoint was overall survival (OS). Adverse events were recorded. The indicative value of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter, isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter were analyzed. Results: Twenty-three patients were enrolled in this study, in which the results of 20 patients were available and analyzed. The median follow-up time was 8.2 (range: 3.2 to 23.1) months. The PFS-6 was 25% and median PFS was 3.7 months (95%CI: 1.85-5.55). According to RANO criteria, 6 patients reached partial response, 9 had stable disease, and 5 patients directly got progression disease without any response. Thus objective response rate (ORR) was 30%. Median OS was 9.2 months (95%CI: 7.27-11.13). Most of treatment-related adverse events were The Common Terminology Criteria for Adverse Events (CTCAE) grade one or two. Decrease of platelet, hypertension and fatigue were common. The molecular biomarker analysis of available tissues showed TERTp wild-type patients (n=11) had longer PFS than TERTp mutated patients (n=7) (6.0 months vs 1.9 months, P=0.02). MGMTp methylated group (n=10) had better trend in response rate than MGMTp unmethylated group (n=8) (30% vs 12.5%, P=0.18), and TERTp wildtype group (n=11) had better trend in response rate compared with TERTp mutation group (n=7) (36.3% vs 14.2%, P=0.32). Conclusion: Bevacizumab plus nitrosoureas regimen could be considered effective and safe in treatment of recurrent high-grade gliomas. Wild-type TERT promoter can indicate longer PFS. MGMTp methylated group and TERTp wild-type group have better trend in response rate.

Key words: Glioma, Bevacizumab, Nitrosoureas, Molecular biomarker