Clinical Cancer Research: Phase II Investigation of TVB-2640 (Denifanstat)with Bevacizumabin Patients with First Relapse High-Grade Astrocytoma (Chen)

William Kelly 1, Adolfo Enrique Diaz Duque 1,Joel Michalek 2, Brandon Konkel 3,L aura Caflisch 3, Yidong Chen 2,Sarath Chand Pathuri 1,Vinu Madhusudanannair-Kunnuparampil 4, John Floyd II 5,and Andrew Brenner 1

ABSTRACT

Purpose: Glioblastoma represents the most common primary brain tumor. Although antiangiogenics are used in the recurrent setting, they do not prolong survival. Glioblastoma is known to upregulate fatty acid synthase(FASN) to facilitate lipid biosynthesis.TVB-2640, a FASN inhibitor, impairs this activity.

Experimental Design: We conducted a prospective,single-center,open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assignedtoTVB-2640(100mg/m2oral daily) plus bevacizumab (10mg/kg iv., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease(PD). The primary endpoint was progression-free survival (PFS).

Results: A total of 25 patients were enrolled. The most frequently reported adverse events (AE)were palmar–plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most were grade 1 or 2 intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56%(complete response,17%; partial response,39%).PFS6forTVB-2640plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB16%;P¼0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test(P¼0.56).

Conclusions: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.

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