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• W2479445948 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." @default.
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• W2479445948 date "2015-09-01" @default.
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• W2479445948 title "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" @default.
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