Reverse swing-M, phase 1 study of repurposing mebendazole in recurrent high-grade glioma.
Adult
Aged
Antiemetics
/ administration & dosage
Antineoplastic Agents
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Brain Neoplasms
/ drug therapy
Drug Repositioning
Female
Glioblastoma
/ drug therapy
Humans
Lomustine
/ administration & dosage
Male
Maximum Tolerated Dose
Mebendazole
/ administration & dosage
Medication Adherence
Middle Aged
Neoplasm Recurrence, Local
/ drug therapy
Ondansetron
/ administration & dosage
Re-Irradiation
Salvage Therapy
/ methods
Temozolomide
/ administration & dosage
Checkpoint
Glioblastoma
High-grade Glioma
Mebendazole
Recurrence
Repurposing
Salvage
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
17
12
2019
revised:
01
04
2020
accepted:
08
04
2020
pubmed:
14
5
2020
medline:
4
5
2021
entrez:
14
5
2020
Statut:
ppublish
Résumé
Relapsed high-grade glioma has dismal outcomes. Mebendazole has shown promising activity against glioma in in-vitro and in-vivo studies. Hence, we undertook a phase 1 study to repurpose mebendazole in the treatment of glioblastoma. We conducted a phase 1 study (accelerated titrated design 4) of mebendazole in patients with recurrent glioblastoma (GBM). Patients eligible for re-irradiation were enrolled in arm A1 (radiation with concurrent temozolomide 75 mg/m 11 patients were enrolled in the whole study. MTD of mebendazole was not reached in arm A1 and C1 and hence the recommended dose for phase 2 was 1600 mg TDS (4800 mg) per day. The MTD of mebendazole in combination with CCNU was 1600 mg TDS (4800 mg) per day and the dose recommended for phase 2 was 800 mg TDS (2400 mg) per day. The three most common adverse events seen in the study were anemia (n = 9, 81.8%), nausea (n = 7, 63.6%), and fatigue (n = 6, 55.5%). The recommended phase 2 dose of mebendazole is 1600 mg TDS with temozolomide and temozolomide-radiation combination while the dose of 800 mg TDS needs to be used with single-agent CCNU.
Sections du résumé
BACKGROUND
Relapsed high-grade glioma has dismal outcomes. Mebendazole has shown promising activity against glioma in in-vitro and in-vivo studies. Hence, we undertook a phase 1 study to repurpose mebendazole in the treatment of glioblastoma.
METHODS
We conducted a phase 1 study (accelerated titrated design 4) of mebendazole in patients with recurrent glioblastoma (GBM). Patients eligible for re-irradiation were enrolled in arm A1 (radiation with concurrent temozolomide 75 mg/m
FINDINGS
11 patients were enrolled in the whole study. MTD of mebendazole was not reached in arm A1 and C1 and hence the recommended dose for phase 2 was 1600 mg TDS (4800 mg) per day. The MTD of mebendazole in combination with CCNU was 1600 mg TDS (4800 mg) per day and the dose recommended for phase 2 was 800 mg TDS (2400 mg) per day. The three most common adverse events seen in the study were anemia (n = 9, 81.8%), nausea (n = 7, 63.6%), and fatigue (n = 6, 55.5%).
INTERPRETATION
The recommended phase 2 dose of mebendazole is 1600 mg TDS with temozolomide and temozolomide-radiation combination while the dose of 800 mg TDS needs to be used with single-agent CCNU.
Identifiants
pubmed: 32400117
doi: 10.1002/cam4.3094
pmc: PMC7333848
doi:
Substances chimiques
Antiemetics
0
Antineoplastic Agents
0
Ondansetron
4AF302ESOS
Lomustine
7BRF0Z81KG
Mebendazole
81G6I5V05I
Temozolomide
YF1K15M17Y
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4676-4685Informations de copyright
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Références
J Natl Cancer Inst. 1997 Aug 6;89(15):1138-47
pubmed: 9262252
Am J Clin Oncol. 2000 Apr;23(2):155-9
pubmed: 10776976
N Engl J Med. 2017 Nov 16;377(20):1954-1963
pubmed: 29141164
J Neurosurg. 2013 Apr;118(4):812-20
pubmed: 23082884
J Neurosurg. 2013 Jun;118(6):1224-31
pubmed: 23495879
Anticancer Res. 1998 Mar-Apr;18(2B):1303-11
pubmed: 9615807
Mol Med. 2017 Apr;23:50-56
pubmed: 28386621
Neuro Oncol. 2011 Sep;13(9):974-82
pubmed: 21764822
Indian J Cancer. 2016 Oct-Dec;53(4):558-561
pubmed: 28485350
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
Clin Cancer Res. 2006 Mar 15;12(6):1928-35
pubmed: 16551879
Lancet Oncol. 2013 May;14(6):e239-48
pubmed: 23639324
Curr Cancer Drug Targets. 2007 Sep;7(6):566-81
pubmed: 17896922
Mol Cancer Ther. 2015 Jan;14(1):3-13
pubmed: 25376612
J Natl Cancer Inst. 2009 May 20;101(10):708-20
pubmed: 19436029
Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):2018-24
pubmed: 21489708
New Bioeth. 2017 Apr;23(1):95-104
pubmed: 28517989
Ecancermedicalscience. 2014 Jul 10;8:443
pubmed: 25075217
Clin Cancer Res. 2015 Aug 1;21(15):3462-3470
pubmed: 25862759
Eur J Clin Pharmacol. 1982;22(2):161-9
pubmed: 7094986
Mol Cancer Res. 2008 Aug;6(8):1308-15
pubmed: 18667591
Cancer. 2019 Sep 15;125(18):3184-3197
pubmed: 31150120
Lancet Oncol. 2009 May;10(5):459-66
pubmed: 19269895
J Clin Oncol. 2005 Dec 1;23(34):8863-9
pubmed: 16314646
Cancer Med. 2020 Jul;9(13):4676-4685
pubmed: 32400117
Br J Clin Pharmacol. 1987 Sep;24(3):390-2
pubmed: 3663452
Int J Clin Pharmacol Ther Toxicol. 1985 Dec;23(12):633-41
pubmed: 4093204
Semin Radiat Oncol. 2014 Oct;24(4):289-98
pubmed: 25219814
J Clin Oncol. 2010 Jun 20;28(18):3048-53
pubmed: 20479391
Neuro Oncol. 2013 Feb;15(2):242-50
pubmed: 23243055
BMC Cancer. 2010 Apr 15;10:143
pubmed: 20398289
Clin Cancer Res. 2002 Sep;8(9):2963-9
pubmed: 12231542