Abstract B13: Biomarker Analyses from Dose Escalation Phase of FASN Inhibitor TVB-2640 Phase 1 Study Shows Target Engagement in Solid Tumor Patients
Authors: O'Farrell Marie , Crowley Richard , Heuer Timothy , Fridlib Marina , Buckley Doug , McCulloch William , Kemble George 
Published: May 2016

TVB-2640 is a potent, reversible and selective fatty acid synthase (FASN) inhibitor currently in Phase 1 in solid tumor patients (study 3V2640-CLIN-002). This study includes biomarker assays to assess pharmacodynamic activity and refine strategies for patient selection. This report focuses on biomarker results from the dose escalation phase to assess pharmacodynamic activity for this first in class agent.

FASN is a central mediator of neoplastic lipogenesis, and uniquely catalyzes the production of palmitate, the building block of long chain fatty acids. Unlike most normal cells, tumor cells frequently have high FASN expression, which correlates with poor prognosis in several tumor types. Tumor cells rely on de novo lipogenesis to produce phospholipids, lipid second messengers, membranes and lipid rafts needed for oncogenic signaling, survival and proliferation, via many pathways including activated RTKs and hormone receptors.

In Phase 1 study 3V2640-CLIN-002 (NCT02223247), 31 patients were enrolled on TVB-2640 monotherapy (oral, once daily) and 13 patients were enrolled in combination with weekly paclitaxel. Plasma TVB-2640 drug levels increased with dose with a half-life of approximately 15 hr. Several complementary biomarker approaches were pursued to investigate FASN pathway inhibition in tumor and surrogate tissues.

(i) Serum was assessed by mass spectrometry-based global metabolomic profiling to screen for changes following TVB-2640 administration. Increased levels of malonyl carnitine were observed after 8 days of TVB-2640 treatment in 9/10 patients tested. The degree of change of malonyl carnitine increased with greater exposure to the drug. Decreased levels of tripalmitin were also observed in 9/10 patients. These changes are consistent with the expected consequences of FASN inhibition. Serum metabolite profiles from rats administered a FASN inhibitor for 5 to 7 days showed similar trends. These data provide evidence of FASN inhibition by TVB-2640, a first in class agent, in the clinic.

(ii) Fresh tumor biopsies were analyzed by immunohistochemistry (IHC) for markers relevant to FASN engagement. In all 4 patients to date with evaluable biopsies, pAKT S473 decreased by 30-50% after 1 cycle of TVB-2640 treatment relative to predose. Total AKT did not change in either of the 2 patients tested. pAKT inhibition has also been observed in preclinical rat xenografts treated with TVB-2640.

(iii) Gene expression analysis by RNA Seq has been initiated in pre and post dose macro-dissected tumor biopsies in a limited number of patients, and in whole blood for up to 13 patients. Preliminary bioinformatics analyses show modulation of several lipid metabolism pathways consistent with preclinical studies.

In conclusion, FASN pathway inhibition has been demonstrated at well tolerated dose levels of TVB-2640 in both tumor and serum from cancer patients. Increased serum malonyl carnitine and decreased levels of palmitate derivatives provide easily accessible biomarkers and show target inhibition. Early tumor biopsy analysis provides evidence of FASN inhibition in the target tissue by IHC and gene expression analysis. These and additional biomarker studies will be conducted in the expansion phase of this study and help guide clinical development of this first in class FASN inhibitor.

Citation Format: Marie O'Farrell, Richard Crowley, Timothy Heuer, Marina Fridlib, Doug Buckley, William McCulloch, George Kemble. Biomarker Analyses from Dose Escalation Phase of FASN Inhibitor TVB-2640 Phase 1 Study Shows Target Engagement in Solid Tumor Patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B13.