Early-Phase Trial of Carboxyamidotriazole Orotate and Temozolomide in Glioblastoma

Key Points

  • The combination was well tolerated, with a carboxyamidotriazole orotate flat dose of 600 mg/d selected for phase II study.
  • Activity of the combination was observed in both previously treated and treatment-naive patient cohorts. 

In a phase Ib trial reported in the Journal of Clinical Oncology, Omuro et al found evidence of activity of carboxyamidotriazole orotate plus temozolomide in patients with recurrent anaplastic gliomas or glioblastoma and previously untreated glioblastoma. Carboxyamidotriazole orotate is an oral inhibitor of non–voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways that has exhibited synergistic effects with temozolomide in glioblastoma models.

Study Details

In cohort 1, 27 patients with recurrent anaplastic gliomas or glioblastoma (n = 16) received escalating doses of carboxyamidotriazole orotate (219–812.5 mg/m2 once daily or a 600-mg fixed once-daily dose) combined with temozolomide (150 mg/m2 on 5 days during each 28-day cycle). In cohort 2 (n = 15), patients with newly diagnosed glioblastoma (1 with anaplastic astrocytoma) received escalating doses of carboxyamidotriazole orotate (219–481 mg/m2 once daily) with radiotherapy and temozolomide at 75 mg/m2, followed by temozolomide at 150–200 mg/m2 on 5 days during each 28-day cycle.

Toxicity

In cohort 1, the most common treatment-related adverse events of any grade were fatigue (52%), nausea (41%), and constipation (37%); no grade 3 or 4 events were observed. No dose-limiting toxicities were observed, and no maximum tolerated dose was reached.

In cohort 2, the most common treatment-related adverse events of any grade were fatigue (67%), nausea (53%), constipation (47%), radiotherapy-related dermatitis (33%), thrombocytopenia (27%), and skin rash (27%). The most common grade 3 event was febrile neutropenia (13%).

No dose-limiting toxicities were observed, and the recommended carboxyamidotriazole orotate dose for phase II study was selected as 600 mg/d as a flat dose. Pharmacokinetic analysis showed that carboxyamidotriazole orotate did not alter temozolomide levels, with therapeutic concentrations being achieved in the tumor and brain.

Activity of the Combination

In cohort 1, responses were observed in 7 (26%) of 27 patients, including 1 complete response, and including responses in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. Among the 15 patients in cohort 2, median progression-free survival was 15 months and median overall survival was not reached over a median follow-up of 28 months; 2-year overall survival was 62%.

Among 9 evaluable patients with measureable disease, response was observed in 3 (33%), with complete response in 1. Gene sequencing showed a high rate of response among EGFR-amplified tumors (P = .005); EGFR amplification or mutation was found in 3 of 6 responders with known EGFR status in cohort 1 and in all 3 responders in cohort 2. Mechanisms of acquired resistance appeared to involve mutations in mismatch-repair genes or the downstream components TSC2, NF1, NF2, PTEN, and PIK3CA.

The investigators concluded, “[Carboxyamidotriazole orotate] can be combined safely with [temozolomide] or chemoradiation in [glioblastoma] and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.”

The study was supported by Tactical Therapeutics and National Institutes of Health.

Elena Pentsova, MD, of the Department of Neurology, Memorial Sloan-Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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