Carboxyamidotriazole orotate (CTO) plus temozolomide (TMZ) was well tolerated in patients with glioma.

  • Major finding: Carboxyamidotriazole orotate (CTO) plus temozolomide (TMZ) was well tolerated in patients with glioma.

  • Approach: CTO plus TMZ achieved responses in refractory and newly diagnosed glioblastoma and anaplastic glioma.

  • Impact: CTO may be safely combined with TMZ or chemoradiation for the treatment of patients with glioma.

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Patients with glioblastoma or anaplastic glioma are generally treated with radiotherapy plus adjuvant temozolomide (TMZ). Preclinical studies have suggested that carboxyamidotriazole orotate (CTO), an inhibitor of non–voltage-dependent calcium channels that modulates various Ca2+-dependent signaling pathways including AKT, RAS, and WNT to produce antitumor activity, may synergize with TMZ in glioblastoma. Omuro and colleagues evaluated the safety and efficacy of TMZ plus escalating doses of CTO in a phase Ib trial of patients with glioblastoma or anaplastic glioma in two cohorts. Twenty-seven patients with heavily pretreated recurrent glioblastoma or anaplastic glioma were treated with CTO plus TMZ in cohort 1, and 15 patients with newly diagnosed glioblastoma or anaplastic glioma were treated with CTO, TMZ, and radiotherapy in cohort 2. The primary objective was to determine the safety, toxicity, and recommended phase II dose of CTO in combination with TMZ. The secondary objective was pharmacokinetic evaluation, and exploratory objectives included assessment of preliminary efficacy. Treatment with CTO plus TMZ was well tolerated with no dose-limiting toxicities in either cohort. No treatment-related grade 3 to 5 adverse events occurred in cohort 1. Cohort 2 had a higher incidence of adverse events due to the higher TMZ dose and concomitant radiotherapy. Pharmacokinetics analysis revealed that TMZ levels were not significantly altered by CTO, and therapeutic concentrations were achieved in the tumor and the brain. In cohort 1, 7 of 27 patients (26%) achieved an objective response, including 1 complete and six partial responses, and the median progression-free survival was 3.1 months. Of the 9 evaluable patients in cohort 2, 3 (33%) achieved objective responses, including 1 complete and 2 partial responses, and the median progression-free survival was 15 months. These findings suggest that combining CTO with TMZ or chemoradiation is well tolerated and has promising antitumor activity in patients with glioblastoma and anaplastic glioma.

Omuro A, Beal K, McNeill K, Young RJ, Thomas A, Lin X, et al. Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas. Science 2018 Apr 20 [Epub ahead of print].

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