LATE BREAKING ABSTRACT: Evidence of activity of a new mechanism of action (MoA): A first-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640, as monotherapy or in combination

H.T. Arkenu, M. Voskoboynik, J. Infante, A. Brenner, M. Patel, E. Borazanci, G. Falchook, L.R. Molife, S. Pant, Emma Dean, L. Pelosof, S. Jones, C. Rubino, W. McCulloch, V. Zhukova-Harrill, G. Kemble, M O'Farrell, H. Burris

    Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

    Abstract

    Background: FASN inhibition is a novel approach to cancer treatment involving the selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an orally bioavailable, first-in-class, small-molecule reversible inhibitor of FASN. Methods: Eligible patients (pts) with adequate bone marrow, hepatic and renal function from 7 US and 4 UK sites were enrolled. Pts with significant cardiovascular or ophthalmological disease and any conditions that might interfere with oral absorption were excluded. TVB-2640 was administered QD p.o. as monotherapy or in combination with paclitaxel 80mg/m2, days 1, 8 and 15 q28. Standard safety assessments, pharmacokinetic (PK) sampling, ophthalmological examinations and 24-hour Holter monitoring for QTc assessments were required. Blood and tumor tissue (archival and/or fresh) for pharmacodynamic (PD) assessments were obtained. Results: In dose escalation, 31 pts were enrolled across 6 monotherapy cohorts and 13 pts in 2 combination cohorts. The MTD was declared at 100mg/m2 once daily continuously for both regimens. DLTs observed in both groups of patients were reversible and consisted of corneal edema (Grade 3, n=2), keratitis and iritis (Grade 2 and 3, n=1 each), probably due to disrupted tear film lipid metabolism, and palmar-plantar erythrodysesthesia or skin peeling (Grade 3, n=3 and Grade 1, n=1). Other toxicities were ≤Grade 2 with only minor GI symptoms seen; Grade 1/2 alopecia was reported by 63% of patients overall. No QTc prolongation was seen. No change in paclitaxel toxicity or the pK parameters of either compound was observed with the combination. One confirmed PR (42% SLD reduction of lesions with 58% drop in CA-125 levels) in a combination-treated pt with peritoneal serous carcinoma was observed. Of 7 previously-treated NSCLC pts, 1 achieved SD for 17 weeks with monotherapy and 2 achieved SD for 24 and 16 weeks with combination treatment (both failed prior taxane therapy). 1/6 heavily pretreated breast pts (TNBC) demonstrated SD for 20 weeks. PD biomarkers have been identified in tumor and serum. In all 4 pts with paired tumor biopsies available so far, decreased pAKT S473 was noted after 1 cycle compared to pretreatment. Global metabolic serum profiling after 8 days of TVB-2640 treatment showed increased levels of malonyl carnitine, a malonyl coA derivative, and decreased tripalmitin, a palmitate derivative, in 9 of 10 pts tested, consistent with FASN inhibition. Conclusion: A monotherapy and combination MTD of TVB-2640 with a manageable toxicity profile has been defined. Encouraging signs of clinical activity have been seen, in monotherapy and in combination with paclitaxel, including one PR and several long-term SDs. PD markers in serum and tumor tissue are also encouraging. Further exploration of biological activity is underway in expansion cohorts.
    Original languageEnglish
    Title of host publication18th ECCO-40th ESMO European Cancer Congress 2015
    Publication statusPublished - Sept 2015
    EventEuropean Cancer Congress - Vienna, Austria
    Duration: 25 Sept 201529 Sept 2015

    Conference

    ConferenceEuropean Cancer Congress
    CityVienna, Austria
    Period25/09/1529/09/15

    Keywords

    • Fatty Acid Synthase Inhibitor
    • Lipid Metabolism

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