Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma

Purpose: Glioblastoma is the most common primary brain tumor. While antiangiogenic agents are used in the recurrent setting, they do not extend survival. Glioblastomas upregulate fatty acid synthase (FASN) to enhance lipid biosynthesis, and TVB-2640, a FASN inhibitor, targets this process.

Patients and Methods: We conducted a prospective, single-center, open-label, phase II study evaluating TVB-2640 in combination with bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assigned to receive either TVB-2640 (100 mg/m², orally daily) plus bevacizumab (10 mg/kg intravenously on Day 1 and Day 15) or bevacizumab monotherapy for the first 28-day cycle, which was used for biomarker analysis. After this initial cycle, all patients were treated with TVB-2640 plus bevacizumab until disease progression or treatment-related toxicity. The primary endpoint was progression-free survival (PFS).

Results: A total of 25 patients were enrolled. The most common adverse events (AEs) were palmar-plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infections, most of which were grade 1 or 2. The overall response rate (ORR) for the combination of TVB-2640 plus bevacizumab was 56% (17% complete response and 39% partial response). PFS at 6 months (PFS6) was 31.4%, significantly higher than the historical PFS6 of 16% with bevacizumab monotherapy (BELOB trial, P = 0.008), meeting the primary endpoint. The 6-month overall survival (OS6) rate was 68%, although the survival difference was not statistically significant (P = 0.56 by log-rank test).

Conclusions: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was well tolerated when combined with bevacizumab. The combination showed a favorable safety profile and promising efficacy signals, supporting the initiation of a larger multicenter trial to further investigate the combination of TVB-2640 and bevacizumab in astrocytoma.