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 a first-in-human dose-escalation study with the oral FASN inhibitor TVB-2640 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as monotherapy and with a taxane. Methods: This completed open-label outpatient study was conducted at 11 sites in the United States and United Kingdom. Patients with previously-treated advanced metastatic solid tumors and adequate performance status and organ function were eligible. TVB-2640 was administered orally daily until PD. Dose escalation initially followed an accelerated titration design that switched to a standard 3 + 3 design after Grade 2 toxicity occurred. Disease-specific cohorts were enrolled at the MTD. Statistical analyses were primarily descriptive. Safety analyses were performed on patients who received at least 1 dose of study drug. (Clinicaltrials.gov identifier NCT02223247) Findings: The study was conducted from 21 November 2013 to 07 February 2017. Overall, 136 patients received TVB-2640, 76 as monotherapy (weight-based doses of 60 mg/m(2) to 240 mg/m(2) and flat doses of 200 and 250 mg) and 60 in combination, (weight-based doses of 60 mg/m(2) to 100 mg/m(2) 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 common TEAEs (n,%) with TVB-2640 monotherapy were alopecia (46;61%), PPE syndrome (35;46%), fatigue (28;37%), decreased appetite (20;26%), and dry skin (17;22%), and 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 case of drug-related pneumonitis occurred with TVB-2640 +paclitaxel; no other treatment-related deaths occurred. Target engagement (FASN inhibition) and inhibition of lipogenesis were demonstrated with TVB-2640. The disease control rate (DCR) with TVB-2640 monotherapy was 42%;no patient treated with monotherapy had a complete or partial response (CR or PR). In combination with paclitaxel, the PR rate was 11% and the DCR was 70%. Responses were seen across multiple tumor types, including in patients with KRAS(MUT) NSCLC, ovarian, and breast cancer. Interpretation: TVB-2640 demonstrated potent FASN inhibition and a predictable and manageable safety profile, primarily characterized by non-serious, reversible adverse events affecting skin and eyes. Further investigation of TVB-2640 in patients with solid tumors, particularly in KRASMUT lung, ovarian, and breast cancer, is warranted. (C) 2021 The Authors. Published by Elsevier Ltd.

Automated summary

The study aimed to determine the MTD and RP2D of oral FASN inhibitor TVB-2640 and evaluate its safety and efficacy in monotherapy and in combination with paclitaxel. Results showed potent FASN inhibition with manageable toxicity primarily affecting skin and eyes, supporting further investigation particularly in KRASMUT lung, ovarian, and breast cancer patients.