First-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640 as monotherapy or in combination - final results of dose escalation.

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 oral, first-in-class, small-molecule reversible inhibitor of FASN that demonstrates in vitro and in vivo anti-tumor effects. We previously reported (EORTC-NCI-AACR 2014: 3 LBA, AACR/ASCO 2015: CT203/ TPS2615) on the design of this trial (NCT02223247) and now report on the final results of the dose escalation phase.MethodsPatients from 7 US and 4 UK sites with adequate bone marrow, hepatic and renal function were enrolled. Patients with significant cardiovascular or ophthalmological disease and any conditions that might interfere with oral absorption were excluded. In addition to standard safety assessments and pharmacokinetic (PK) sampling, ophthalmological examinations and 24-hour Holter monitoring for QTc assessments were performed. Blood and tumor tissue (archival and/or fresh) for various pharmacodynamic (PD) assessments were obtained.ResultsThirty-one patients were enrolled in 6 monotherapy cohorts (60 mg/m2 to 250 mg flat dose) and 13 patients were enrolled in 2 combination cohorts (200 and 250 mg flat dose) in combination with weekly paclitaxel (80 mg/m2, days 1, 8 and 15 q 28 days). Plasma TVB-2640 drug levels increased with dose, with a half-life of approximately 15 hr. The MTD was declared at 100 mg/m2 for both schedules. DLTs observed in both mono- and combination patients were reversible and consisted of corneal edema (Grade 3, n=2), keratitis and iritis (Grade 2 and 3, n=1 each), probably a consequence of disrupted tear film lipid metabolism, and palmar-plantar erythrodysesthesia or skin peeling (Grade 3, n=3 and Grade 1, n=1). Other toxicities were mild (≤ Grade 2) and only minor GI symptoms were observed; alopecia was reported by 63% of patients overall. No enhancement of known paclitaxel toxicity was observed when given in combination with TVB-2640. Of the 7 NSCLC patients accrued so far, 1 achieved SD for 17 weeks with monotherapy and 2 patients treated in combination with paclitaxel had SD for 24 and 21 weeks respectively. One of three breast cancer patients (histology: triple negative) treated in combination had SD for 20 weeks. One confirmed PR was seen in a combination-treated patient who had peritoneal serous carcinoma with a 42% reduction in tumor load and 58% reduction in CA-125 levels. PD biomarkers have been identified in tumor and in serum. In all four patients with paired tumor biopsies, decreased pAKT S473 was observed after 1 cycle compared to pretreatment biopsies. Global metabolic profiling of serum showed increased levels of malonyl carnitine, a malonyl coA derivative, and decreased tripalmitin, a palmitate derivative, in 9 of 10 patients tested, after 8 days of TVB-2640 treatment. These changes are consistent with FASN inhibition.SummaryContinuously administered, oral TVB-2640 demonstrated a tolerated dose and schedule with a manageable toxicity profile in association with encouraging signs of preliminary activity both as monotherapy and in combination with paclitaxel. PD analyses reveal engagement of the target in both tumor and surrogate tissue. Further exploration of biological activity in various specific tumor types is now underway in expansion cohorts at the MTD using both schedules.