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

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

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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 Goblet Glasses 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/m2 to 240 mg/m2 and flat doses of 200 and 250 mg) and 60 in combination, (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 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 KRASMUT NSCLC, ovarian, and breast cancer.Interpretation: TVB-2640 demonstrated potent FASN inhibition and a predictable and manageable safety profile, Dessert Syrup 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.Funding: This trial was funded by 3-V Biosciences, Inc.(now known as Sagimet Biosciences Inc.).