First-in-human investigation of the oral first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640.

Abstract

TPS2615 Background: FASN is a central mediator of neoplastic lipogenesis. It catalyzes the production of palmitate, the building block of long chain fatty acids needed to support cancer cell signaling and proliferation. Tumor cells have more dependence on de novo lipogenesis than normal cells, and express higher levels of FASN. Several studies have shown a correlation between high levels of FASN expression and both advanced disease stage and poorer prognosis in patients. The combination of these observations provides the rationale for FASN inhibition as an antitumor therapy. TVB-2640 is a potent, reversible and selective fatty acid synthase (FASN) inhibitor currently in its first Phase 1 study (3V2640-CLIN-002) in patients with refractory solid tumors (NCT02223247), EORTC 2014 Abstract number: 3 LBA. Methods: TVB-2640 is administered in monotherapy orally once daily continuously on a 21 day cycle to assess dose-limiting toxicities (DLT). An accelerated dose-escalation method was used initially with single-patient cohorts and 100% dose escalations planned until NCI-CTCAE toxicity ≥ Grade 2 was encountered. Thereafter, the classical “3 + 3” design was used. Additionally, exploration of combination therapy using TVB-2640 co-administered with a taxane has begun. Eligibility includes adult patients with adequate bone marrow, hepatic and renal function and other standard Phase I characteristics. Patients with significant cardiovascular, ophthalmological disease, or any conditions that might interfere with oral absorption are excluded. In addition to standard safety assessments and pharmacokinetic (PK) sampling (over 24 hours on Days 1 and 8), specialist ophthalmological examinations and 24-hour Holter monitoring for QTc assessments are required. Tumor tissue (archival and/or fresh) is being obtained to assess the consequences of FASN inhibition on neoplastic lipogenesis and a pharmacodynamic effect has been evaluated by measuring metabolite changes in patient sera. Clinical trial information: NCT02223247.