Abstract CT203: Report of a first-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640
Authors: Patel Manish , Infante Jeffrey , Von Hoff Daniel , Jones Suzanne , Burris Howard , Brenner Andrew , McCulloch William , Zhukova-Harrill Valentina , Kemble George , Parsey Merdad 
Published: August 2015

Abstract
FASN inhibition is a novel approach to cancer treatment involving the selective disruption of palmitate biosynthesis that, in tumor cells, causes changes in cell signaling, sensitivity to chemotherapeutic agents, and apoptosis in addition to other effects. TVB-2640 is an oral, first-in-class, small-molecule reversible inhibitor of FASN that demonstrates in vitro and in vivo anti-tumor effects with an acceptable non-clinical safety profile.
This is a dose-escalation study (NCT02223247) in patients with metastatic or advanced-stage malignant disease refractory to standard therapy and for whom no therapy exists that would be curative or might provide significant benefit. TVB-2640 was administered once daily on a 21 day cycle to assess dose-limiting toxicities (DLT). An accelerated dose-escalation method was used with single-patient cohorts with 100% dose escalations until NCI-CTCAE toxicity ≥ Grade 2 was encountered. Eligibility included adult patients with adequate bone marrow, hepatic and renal function. Patients with significant cardiovascular or ophthalmological disease and any conditions that might interfere with oral absorption were excluded. In addition to standard safety and PK assessments, specialist ophthalmological examinations and 24-hour Holter monitoring for QTc assessments were required. Blood, serum and tumor tissue (archival and/or fresh) for pharmacodynamic assessments, including mRNA expression profiles, were obtained.
Twenty patients were enrolled across 4 dose levels, 60 mg/m2 (n = 7), 80 mg/m2 (n = 3), 120 mg/m2 (n = 6), and 240 mg/m2 (n = 4). DLTs of reversible corneal edema and iritis, believed to be a consequence of disrupted tear film lipid metabolism, were observed in two patients at 240 mg/m2, leading to further exploration of lower dose levels. Other toxicities have included palmar-plantar erythrodysaesthesia and/or peeling with minor GI symptoms and alopecia. No QTc prolongation has been observed to date. One patient had a paradoxical increase in triglycerides. TVB-2640 has shown excellent oral bioavailability PK in man; plasma exposure generally increases with increasing dose. A preliminary mean half-life of approximately 16 hrs at steady state has been observed, consistent with once a day administration. mRNA changes in whole blood are consistent with target engagement. In addition, key FASN-dependent signaling pathways were inhibited in the tumor tissue of one patient following dosing. Additional IHC and gene expression analysis of pre and post-dose tumor biopsies is ongoing.
In this ongoing first in human trial we defined the PK and safety profile of the novel FASN inhibitor TVB-2640. Human exposures at all dose levels exceed those predicted to be efficacious in mouse preclinical models. 120 mg/m2 exceeds the MTD and the recommended continuous daily dose for future studies remains under study. Combination with chemotherapeutic agents is being examined.
Citation Format: Manish Patel, Jeffrey Infante, Daniel Von Hoff, Suzanne Jones, Howard Burris, Andrew Brenner, William McCulloch, Valentina Zhukova-Harrill, George Kemble, Merdad Parsey. Report of a first-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT203. doi:10.1158/1538-7445.AM2015-CT203