Abstract 2675: Biomarker and PK/PD analyses of first in class FASN inhibitor TVB-2640 in a first-in-human phase 1 study in solid tumor patients

Abstract

Abstract TVB-2640 is a potent, reversible and selective fatty acid synthase (FASN) inhibitor currently in its first Phase 1 study (3V2640-CLIN-002) in solid tumor patients. This study includes biomarker assays for this first in class agent to assess pharmacodynamic activity and refine strategies for patient selection. We describe translational approaches and report early Phase 1 data on FASN biomarkers, in tumor, serum and surrogate tissues such as PBMC and whole blood. FASN is a central mediator of neoplastic lipogenesis. FASN uniquely catalyzes the production of palmitate, the building block of long chain fatty acids, providing a mechanism to convert glucose into lipids needed to support cancer cell signaling and proliferation. Tumor cells have increased 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. FASN plays several roles in cancer cell signaling, including production of phospholipids, alteration of membrane architecture, formation of lipid rafts and the subsequent assembly of signaling molecules in microdomains juxtaposed to the membrane. FASN is upregulated by RTK signaling and also by androgen and estrogen signaling. The profile of FASN expression was characterized by IHC across several hundred archival human tumors and sera (unmatched) across 8 different tumor types. Highest FASN expression by IHC was observed in colorectal, prostate and bladder tumors, with a similar rank ordering for serum with NSCLC and endometrial also among the highest. Normal donors had significantly lower serum levels. Follow up studies are being conducted to investigate the effect of FASN inhibitors on secreted FASN, and its use as a biomarker. Seventeen patients have been enrolled in 3V2640-CLIN-002, and four dose levels of TVB-2640 have been tested to date as monotherapy. PK data show a mean half-life of approximately 16.5 hours following oral administration. Plasma Cmax and AUC increase with dose on day 1, with some overlap between the two highest dose levels at steady state. Several exploratory biomarker analyses have been initiated. Tumor IHC data are available for one patient, and decreased pS6 S240/244 and pAKTS473 were observed after TVB-2640 administration. Secreted proteins such as FASN, VEGF and related proteins in serum are being assessed by ELISA and PK/PD analysis will be shown. A serum metabolomics screen has been initiated to assess changes in lipids and related metabolites. These translational and clinical biomarker assessments inform on FASN biology and clinical development of the first in class FASN inhibitor TVB-2640. Citation Format: Marie O'Farrell, Richard Crowley, Timothy S. Heuer, Doug Buckley, Chris M. Rubino, William McCulloch, George Kemble. Biomarker and PK/PD analyses of first in class FASN inhibitor TVB-2640 in a first-in-human phase 1 study in solid tumor patients. [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 2675. doi:10.1158/1538-7445.AM2015-2675