Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
05
02
2021
accepted:
13
07
2021
revised:
13
07
2021
pubmed:
14
8
2021
medline:
23
3
2022
entrez:
13
8
2021
Statut:
ppublish
Résumé
PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.
Identifiants
pubmed: 34385668
doi: 10.1038/s41436-021-01290-y
pii: S1098-3600(21)05436-8
pmc: PMC8631579
doi:
Substances chimiques
2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
0
Imidazoles
0
Oxazepines
0
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2433-2442Informations de copyright
© 2021. The Author(s).
Références
N Engl J Med. 2019 May 16;380(20):1929-1940
pubmed: 31091374
Cancer Discov. 2019 Apr;9(4):482-491
pubmed: 30867161
J Clin Epidemiol. 1998 Nov;51(11):1013-23
pubmed: 9817119
J Clin Oncol. 2008 Jan 10;26(2):190-5
pubmed: 18182661
Clin Cancer Res. 2018 Sep 15;24(18):4380-4387
pubmed: 29793946
Genet Med. 2019 May;21(5):1189-1198
pubmed: 30270358
Contemp Clin Trials. 2016 Mar;47:217-27
pubmed: 26825023
J Pediatr. 2015 Apr;166(4):1048-54.e1-5
pubmed: 25681199
Clin Genet. 2019 Jul;96(1):102-103
pubmed: 31012097
J Med Chem. 2013 Jun 13;56(11):4597-610
pubmed: 23662903
Nature. 2018 Jun;558(7711):540-546
pubmed: 29899452
Am J Med Genet C Semin Med Genet. 2016 Dec;172(4):402-421
pubmed: 27860216
Mol Cancer Ther. 2014 Nov;13(11):2477-88
pubmed: 25323681
Neurogenetics. 2018 May;19(2):77-91
pubmed: 29549527
JAMA Oncol. 2019 Feb 1;5(2):e184475
pubmed: 30543347
Pediatr Dermatol. 2017 Nov;34(6):e317-e320
pubmed: 29144050
Am J Med Genet A. 2015 Feb;167A(2):287-95
pubmed: 25557259
Med Care. 1992 Jun;30(6):473-83
pubmed: 1593914
Rev Chil Pediatr. 2019 Dec;90(6):662-667
pubmed: 32186590
Clin Cancer Res. 2019 May 15;25(10):2975-2987
pubmed: 30723140