A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921).
Adolescent
Animals
Antineoplastic Agents
/ administration & dosage
Azepines
/ administration & dosage
Biomarkers, Tumor
Child
Child, Preschool
Disease Models, Animal
Drug Resistance, Neoplasm
/ genetics
Female
Humans
Leukemia
/ diagnosis
Male
Mice
Multimodal Imaging
Neoplasms
/ diagnosis
Protein Kinase Inhibitors
/ administration & dosage
Pyrimidines
/ administration & dosage
Recurrence
Retreatment
Treatment Outcome
Xenograft Model Antitumor Assays
Young Adult
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
26
11
2018
revised:
20
12
2018
accepted:
14
02
2019
pubmed:
20
2
2019
medline:
7
7
2020
entrez:
20
2
2019
Statut:
ppublish
Résumé
Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Alisertib (80 mg/m A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
Identifiants
pubmed: 30777875
pii: 1078-0432.CCR-18-2675
doi: 10.1158/1078-0432.CCR-18-2675
pmc: PMC6897379
mid: NIHMS1522277
doi:
Substances chimiques
Antineoplastic Agents
0
Azepines
0
Biomarkers, Tumor
0
MLN 8237
0
Protein Kinase Inhibitors
0
Pyrimidines
0
Banques de données
ClinicalTrials.gov
['NCT01154816']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3229-3238Subventions
Organisme : NCI NIH HHS
ID : UM1 CA228823
Pays : United States
Organisme : NCI NIH HHS
ID : N01 CM042216
Pays : United States
Organisme : NCI NIH HHS
ID : N01CM42216
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180899
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180886
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA097452
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
Références
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
J Clin Oncol. 2014 Jan 1;32(1):44-50
pubmed: 24043741
Clin Cancer Res. 2011 Dec 15;17(24):7614-24
pubmed: 22016509
Cancer Cell. 2016 Feb 8;29(2):159-72
pubmed: 26859456
Cancer Chemother Pharmacol. 2011 Nov;68(5):1291-304
pubmed: 21448591
Carcinogenesis. 2004 Nov;25(11):2149-53
pubmed: 15271853
Cancer Cell. 2013 Jul 8;24(1):75-89
pubmed: 23792191
Clin Cancer Res. 2008 Mar 15;14(6):1639-48
pubmed: 18347165
Cancer Epidemiol. 2014 Apr;38(2):111-7
pubmed: 24252226
Clin Cancer Res. 2012 Sep 1;18(17):4764-74
pubmed: 22753585
Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):1144-52
pubmed: 21050672
J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2369-73
pubmed: 20685183
Drug Metab Lett. 2014 Jul;7(2):96-104
pubmed: 24484538
Nat Genet. 2003 Aug;34(4):403-12
pubmed: 12881723
Gynecol Oncol. 2012 Oct;127(1):63-9
pubmed: 22772063
J Clin Oncol. 2015 Jul 20;33(21):2399-404
pubmed: 26077240
Nat Rev Drug Discov. 2009 Jul;8(7):547-66
pubmed: 19568282
Cancer Epidemiol Biomarkers Prev. 2004 Oct;13(10):1589-94
pubmed: 15466974
Biochem Mol Biol Int. 1998 Sep;46(1):21-6
pubmed: 9784835
PLoS One. 2014 Sep 30;9(9):e108758
pubmed: 25268132
J Clin Oncol. 2003 Dec 15;21(24):4642-9
pubmed: 14673054
J Pediatr Surg. 2014 Jan;49(1):159-65
pubmed: 24439602
Eur J Cancer. 1995;31A(2):256-61
pubmed: 7718334
Pediatr Blood Cancer. 2013 Nov;60(11):1809-16
pubmed: 23788275
Pediatr Blood Cancer. 2010 Jul 15;55(1):26-34
pubmed: 20108338
J Neurooncol. 2012 May;107(3):517-26
pubmed: 22246202
Nat Rev Cancer. 2017 Apr;17(4):254-268
pubmed: 28104906
Pediatr Blood Cancer. 2007 Dec;49(7):928-40
pubmed: 17066459
J Clin Pharmacol. 2015 Mar;55(3):336-47
pubmed: 25302940
Clin Cancer Res. 2012 Nov 1;18(21):6058-64
pubmed: 22988055
Lancet Oncol. 2015 Apr;16(4):395-405
pubmed: 25728526
Leukemia. 2013 Mar;27(3):560-8
pubmed: 22940834
Leuk Res Rep. 2014 Jul 05;3(2):58-61
pubmed: 25068104
Clin Cancer Res. 2018 Dec 15;24(24):6142-6149
pubmed: 30093449
J Clin Oncol. 2016 Apr 20;34(12):1368-75
pubmed: 26884555
Invest New Drugs. 2014 Dec;32(6):1181-7
pubmed: 24879333
J Natl Cancer Inst. 2002 Sep 4;94(17):1320-9
pubmed: 12208897
PLoS One. 2014 Mar 05;9(3):e90328
pubmed: 24598702
Nat Rev Mol Cell Biol. 2001 Jan;2(1):21-32
pubmed: 11413462