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.
Biomarkers
Breast cancer
Clinical trials
Drug mechanisms
Gynecological cancers
Lung cancer
Pharmacology
Small molecule agents
Journal
EClinicalMedicine
ISSN: 2589-5370
Titre abrégé: EClinicalMedicine
Pays: England
ID NLM: 101733727
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
entrez:
19
4
2021
pubmed:
20
4
2021
medline:
20
4
2021
Statut:
epublish
Résumé
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. 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). 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 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 This trial was funded by 3-V Biosciences, Inc. (now known as Sagimet Biosciences Inc.).
Sections du résumé
BACKGROUND
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
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
RESULTS
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
INTERPRETATION
CONCLUSIONS
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
FUNDING
BACKGROUND
This trial was funded by 3-V Biosciences, Inc. (now known as Sagimet Biosciences Inc.).
Identifiants
pubmed: 33870151
doi: 10.1016/j.eclinm.2021.100797
pii: S2589-5370(21)00077-8
pmc: PMC8040281
doi:
Banques de données
ClinicalTrials.gov
['NCT02223247']
Types de publication
Journal Article
Langues
eng
Pagination
100797Informations de copyright
© 2021 The Authors.
Références
Biochem Biophys Res Commun. 2015 Aug 7;463(4):612-7
pubmed: 26043686
J Biol Chem. 2006 Apr 28;281(17):12112-22
pubmed: 16507569
Apoptosis. 2017 Jun;22(6):865-876
pubmed: 28386750
Histol Histopathol. 2017 Jul;32(7):687-698
pubmed: 27714708
J Clin Oncol. 2010 Sep 1;28(25):3958-64
pubmed: 20679621
J Infect Chemother. 2010 Oct;16(5):340-4
pubmed: 20354889
PLoS One. 2012;7(4):e33738
pubmed: 22485149
JAMA Oncol. 2016 Jun 1;2(6):805-12
pubmed: 27100819
Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):779-84
pubmed: 25561545
Clin Lung Cancer. 2002 Jul;4(1):52-6
pubmed: 14653877
Mol Cancer Ther. 2008 Feb;7(2):263-70
pubmed: 18281512
Arch Bronconeumol. 2014 Jan;50(1):45
pubmed: 24074747
Cell Host Microbe. 2012 Feb 16;11(2):140-52
pubmed: 22341463
Oncology. 2003;65(3):224-8
pubmed: 14657596
Future Oncol. 2010 Apr;6(4):551-62
pubmed: 20373869
J Transl Med. 2015 May 07;13:146
pubmed: 25947066
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
Nature. 2019 Dec;576(7787):482-486
pubmed: 31827279
J Chemother. 2017 Apr;29(2):113-117
pubmed: 25978147
Expert Opin Drug Discov. 2016 Dec;11(12):1187-1199
pubmed: 27701891
JCI Insight. 2019 Jul 9;5:
pubmed: 31287803
BMC Clin Pathol. 2014 Jan 14;14(1):3
pubmed: 24422874
J Lipid Res. 2013 Mar;54(3):776-85
pubmed: 23319743
Nat Rev Cancer. 2007 Oct;7(10):763-77
pubmed: 17882277
Ther Adv Med Oncol. 2017 Sep;9(9):589-597
pubmed: 29081842
EBioMedicine. 2017 Feb;16:51-62
pubmed: 28159572
EBioMedicine. 2015 Jul 02;2(8):808-24
pubmed: 26425687
Ann Pharmacother. 1997 Dec;31(12):1471-4
pubmed: 9416383
Clin Oncol (R Coll Radiol). 2015 Aug;27(8):483-4
pubmed: 25911197
Int J Biochem Mol Biol. 2011 Jan 1;2(1):89-98
pubmed: 21331354
Tumori. 2015 Jun 25;101(3):e92-5
pubmed: 25908033
Oncotarget. 2015 Aug 7;6(22):18891-904
pubmed: 25970773
Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4300-4305
pubmed: 28400509