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

Abstract

Purpose: Glioblastoma represents the most common prim-Results: A total of 25 patients were enrolled. The most frequently ary brain tumor. Although antiangiogenics are used in the reported adverse events (AE) were palmar–plantar erythrodysestherecurrent setting, they do not prolong survival. Glioblastoma sia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most is known to upregulate fatty acid synthase (FASN) to facilitate were grade 1 or 2 in intensity. The overall response rate (ORR) for lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this TVB-2640 plus bevacizumab was 56% (complete response, 17%; activity. partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was Experimental Design: We conducted a prospective, single-cen-31.4%. This represented a statistically significant improvement in PFS6 ter, open-label, unblinded, phase II study of TVB-2640 plus bevover historical bevacizumab monotherapy (BELOB 16%; P ¼ 0.008) acizumab in patients with recurrent high-grade astrocytoma. and met the primary study endpoint. The observed OS6 was 68%, with Patients were randomly assigned to TVB-2640 (100 mg/m2 oral survival not reaching significance by log-rank test (P ¼ 0.56). daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizuConclusions: In this phase II study of relapsed high-grade mab monotherapy for cycle 1 only (28 days) for biomarker analysis. astrocytoma, TVB-2640 was found to be a well-tolerated oral drug Thereafter, all patients received TVB-2640 plus bevacizumab until that could be safely combined with bevacizumab. The favorable treatment-related toxicity or progressive disease (PD). The primary safety profile and response signals support the initiation of a larger endpoint was progression-free survival (PFS). multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.