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

Abstract

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/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 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 KRAS^MUT lung, ovarian, and breast cancer, is warranted.

Funding: This trial was funded by 3-V Biosciences, Inc. (now known as Sagimet Biosciences Inc.).

Keywords: Biomarkers; Breast cancer; Clinical trials; Drug mechanisms; Gynecological cancers; Lung cancer; Pharmacology; Small molecule agents.

Fig. 1

Dose cohorts.

Fig. 2

CONSORT diagram.

Fig. 3

Dose-normalized AUC_0–24 by Dose, Stratified by PK Day. TVB-2640 levels were measured in patient sera on C1D1 (left panel) and on C1D8 (steady state) (right panel). The AUC_0–24 was calculated for each patient and is shown normalized to a dose of 150 mg once daily. The horizontal line is the median, box shows the 25th-75th percentiles and whiskers extend to the 5th and 95th percentiles. On Day 1, n of 14, 74, 36 and 8 at 100, 150, 200 and 250 mg respectively. At steady state, n of 14, 65, 35 and 7 at 100, 150, 200 and 250 mg respectively.

Fig. 4

TVB-2640 Significantly increases Malonyl Carnitine and Decreases Tripalmitin and Sebum Triglycerides and Sapienic Acid, Indicating Inhibition of FASN Enzymatic Activity. A) Model of FASN pathway activity and proposed impact of TVB-2640. B) MC levels in patient sera. Relative levels of MC are shown from Metabolon data; considered to be a semi-quantitative assay where levels for each samples were normalized to the median of that run (n = 49 pts in 3 runs, with all samples from a given patient assayed on the same run). Whiskers represent 10th and 90th percentile, with median and mean indicated by a line and + respectively. Mean/median normalized levels on C1D1 and C1D8 were 0•59/0•52 and 2•26/1•67 respectively. C) Tripalmitin levels in patient sera. Mol% of total triglyceride data are included for all patients analyzed (n = 49). Whiskers represent 10th and 90th percentile, with median and mean indicated by a line and + respectively. Mean/median normalized levels on C1D1 and C1D8/15 were 26•09/25•89 and 22•68/23•27 respectively. D) Effect of TVB-2640 on sebum triglyceride levels and E) Effect of TVB-2640 on sebum sapienic acid levels. Relative levels of MC are shown from Metabolon data. Fold change is the relative change in analyte of interest at the on-treatment timepoint indicated, compared to baseline (C1D1), for monotherapy or combination treatment. The graphs show the measured results and the fold change is a calculation based on the median values. This has been added to the figure legend. E) Effect of TVB-2640 on sebum sapienic acid levels. For D) and E), fold change is the relative change in analyte of interest at the on-treatment timepoint indicated, compared to baseline (C1D1), for monotherapy or combination treatment. The graphs show the measured results and the fold change is a calculation based on the median values.

Fig. 5

Median Time to Progression among Monotherapy and Combination Therapy Patients with KRAS^MUT versus KRAS^WT Non-small Cell Lung, Breast, and Ovarian Cancer. Median time to progression is presented in weeks by tumor type for both KRAS^WT (yellow bars) and KRAS^MUT (green bars) NSCLC as well as breast (pink bar) and ovarian (blue bar) cancer. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Serum FASN Levels Among Monotherapy and Combination Therapy Patients, by Best Response. Serum FASN levels were measured by ELISA pre-dose (C1D1) in monotherapy (left panel) or combination (right panel) patients. FASN levels are defined as high (> 10 ng/ml) or low (< 10 ng/ml), and plotted against time on study for each patient. PD patients are represented by the red color, and stable disease or PR patients are represented by the green color. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)