Synapse - Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas

Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas Journal Article

Authors:	Omuro, A.; Beal, K.; McNeill, K.; Young, R. J.; Thomas, A.; Lin, X.; Terziev, R.; Kaley, T. J.; DeAngelis, L. M.; Daras, M.; Gavrilovic, I. T.; Mellinghoff, I.; Diamond, E. L.; McKeown, A.; Manne, M.; Caterfino, A.; Patel, K.; Bavisotto, L.; Gorman, G.; Lamson, M.; Gutin, P.; Tabar, V.; Chakravarty, D.; Chan, T. A.; Brennan, C. W.; Garrett-Mayer, E.; Karmali, R. A.; Pentsova, E.
Article Title:	Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas
Abstract:	Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non–voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine–DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors (P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population. © 2018 by American Society of Clinical Oncology.
Journal Title:	Journal of Clinical Oncology
Volume:	36
Issue:	17
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2018-06-10
Start Page:	1702
End Page:	1709
Language:	English
DOI:	10.1200/jco.2017.76.9992
PROVIDER:	scopus
PMCID:	PMC5993168
PUBMED:	29683790
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85048191778&doi=10.1200%2fJCO.2017.76.9992&partnerID=40&md5=54a7e4e560af0a8fa07799deb599bc7f
Notes:	Krishnaben Patel's first name is abbreviated to Krishna in the original publication -- Conference Paper -- Export Date: 2 July 2018 -- Source: Scopus