First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors

Background: We conducted an initial-in-human dose-escalation study using the dental FASN inhibitor TVB-2640 to look for the maximum tolerated dose (MTD) and suggested phase 2 dose (RP2D), as monotherapy with a taxane.

Methods: This completed open-label outpatient study was conducted at 11 sites within the U . s . States and Uk. Patients with formerly-treated advanced metastatic solid tumors and sufficient performance status and organ function were qualified. TVB-2640 was administered orally daily until PD. Dose escalation initially adopted an faster titration design that switched to some standard 3 3 design after Grade 2 toxicity happened. Disease-specific cohorts were enrolled in the MTD. Record analyses were mainly descriptive. Safety analyses were performed on patients who received a minimum of 1 dose of study drug. ( identifier NCT02223247).

Findings: The research was conducted from 21 November 2013 to 07 Feb 2017. Overall, 136 patients received TVB-2640, 76 as monotherapy (weight-based doses of 60 mg/m2 to 240 mg/m2 and flat doses of 200 and 250 mg) and 60 together, (weight-based doses of 60 mg/m2 to 100 mg/m2 and flat dose of 200 mg) (55 paclitaxel, 5 docetaxel). DLTs with TVB-2640 were reversible skin and ocular effects. The MTD/RP2D was 100 mg/m2. The most typical TEAEs (n,%) with TVB-2640 monotherapy were alopecia (46 61%), PPE syndrome (35 46%), fatigue (28 37%), decreased appetite (20 26%), and dried-out skin (17 22%), with TVB-2640 paclitaxel were fatigue (29 53%), alopecia (25 46%), PPE syndrome (25 46%), nausea (22 40%), and peripheral neuropathy (20 36%). One fatal situation of drug-related pneumonitis happened with TVB-2640 paclitaxel not one other treatment-related deaths happened. Target engagement (FASN inhibition) and inhibition of lipogenesis were shown with TVB-2640. The condition control rate (DCR) with TVB-2640 monotherapy was 42% no patient given monotherapy were built with a complete or partial response (CR or PR). In conjunction with paclitaxel, the PR rate was 11% and also the DCR was 70%. Responses were seen across multiple tumor types, including in patients with KRASMUT NSCLC, ovarian, and cancer of the breast.

Interpretation: TVB-2640 shown potent FASN inhibition along with a foreseeable and manageable safety profile, mainly characterised by non-serious, reversible adverse occasions affecting skin and eyes. Further analysis of TVB-2640 in patients with solid tumors, specifically in KRASMUT lung, ovarian, and cancer of the breast, is warranted.