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

Autor:	Kelly W; Mays Cancer Center at UT Health San Antonio, San Antonio, Texas., Diaz Duque AE; Mays Cancer Center at UT Health San Antonio, San Antonio, Texas., Michalek J; Department of Population Health Sciences, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas., Konkel B; Hematology and Oncology, Florida Cancer Specialists, St. Petersburg, Florida., Caflisch L; Hematology and Oncology, Florida Cancer Specialists, St. Petersburg, Florida., Chen Y; Department of Population Health Sciences, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas., Pathuri SC; Mays Cancer Center at UT Health San Antonio, San Antonio, Texas., Madhusudanannair-Kunnuparampil V; The START Center for Cancer Care, Hematology and Oncology, San Antonio, Texas., Floyd J; Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas., Brenner A; Mays Cancer Center at UT Health San Antonio, San Antonio, Texas.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Jul 05; Vol. 29 (13), pp. 2419-2425.
DOI:	10.1158/1078-0432.CCR-22-2807
Abstrakt:	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. Patients and Methods: 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 assigned to TVB-2640 (100 mg/m2 oral daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) 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 in intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56% (complete response, 17%; partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%; P = 0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test (P = 0.56). 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. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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