Show simple item record

dc.contributor.authorFalchook, G.
dc.contributor.authorInfante, J.
dc.contributor.authorArkenau, H. T.
dc.contributor.authorPatel, M. R.
dc.contributor.authorDean, Emma J
dc.contributor.authorBorazanci, E.
dc.contributor.authorBrenner, A.
dc.contributor.authorCook, Natalie
dc.contributor.authorLopez, J.
dc.contributor.authorPant, S.
dc.contributor.authorFrankel, A.
dc.contributor.authorSchmid, P.
dc.contributor.authorMoore, K.
dc.contributor.authorMcCulloch, W.
dc.contributor.authorGrimmer, K.
dc.contributor.authorO'Farrell, M.
dc.contributor.authorKemble, G.
dc.contributor.authorBurris, H.
dc.date.accessioned2021-05-18T08:48:09Z
dc.date.available2021-05-18T08:48:09Z
dc.date.issued2021en
dc.identifier.citationFalchook G, Infante J, Arkenau H-T, Patel MR, Dean E, Borazanci E, et al. 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. EClinicalMedicine. 2021 Apr;34:100797.en
dc.identifier.pmid33870151en
dc.identifier.doi10.1016/j.eclinm.2021.100797en
dc.identifier.urihttp://hdl.handle.net/10541/624019
dc.description.abstractBackground: 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 KRASMUT 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.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1016/j.eclinm.2021.100797en
dc.titleFirst-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 tumorsen
dc.typeArticleen
dc.contributor.departmentSarah Cannon Research Institute at HealthONE, 1800 Williams St Ste 300, Denver, CO, 80218, United Stateen
dc.identifier.journalEClinicalMedicineen
dc.description.noteen
refterms.dateFOA2021-05-19T08:37:38Z


Files in this item

Thumbnail
Name:
33870151.pdf
Size:
1.523Mb
Format:
PDF
Description:
From UNPAYWALL

This item appears in the following Collection(s)

Show simple item record