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.

中文翻译：

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Carboxyamidotriazole Orotate 和 Temozolomide 治疗复发性和新诊断的胶质母细胞瘤和其他间变性胶质瘤的多中心 IB 期试验

目的羧胺三唑乳清酸盐 (CTO) 是一种新型的非电压依赖性钙通道的口服抑制剂，在胶质母细胞瘤 (GBM) 模型中具有多种细胞信号通路的调节作用和与替莫唑胺 (TMZ) 的协同作用。我们进行了一项 IB 期研究，将 CTO 与 GBM 中的两个标准 TMZ 计划相结合。方法 在队列 1 中，复发性间变性胶质瘤或 GBM 患者接受递增剂量的 CTO（219 至 812.5 mg/m2 每日一次或 600 mg 每日一次固定剂量）联合 TMZ（每 28 天期间 150 mg/m2 5 天）循环）。在队列 2 中，新诊断的 GBM 患者接受了剂量递增的 CTO（219 至 481 mg/m2/d，每天一次）和放疗和 TMZ 75 mg/m2/d，然后是 TMZ 150 mg 至 200 mg/m2，在治疗期间 5 天每 28 天一个周期。结果共纳入47例患者。治疗耐受性良好；毒性包括疲劳、便秘、恶心和低磷血症。药代动力学表明 CTO 没有改变 TMZ 水平；在肿瘤和脑中达到治疗浓度。未观察到剂量限制性毒性；推荐的 II 期剂量为 600 mg/d 平剂量。队列 1 (n = 27) 中的活动信号包括部分 (n = 6) 和完全 (n = 1) 反应，包括未甲基化的 O6-甲基鸟嘌呤-DNA 甲基转移酶和贝伐单抗难治性肿瘤。在队列 2（n = 15）中，中位无进展生存期为 15 个月，中位总生存期未达到（中位随访，28 个月；2 年总生存期，62%）。基因测序揭示了 EGFR 扩增肿瘤的高反应率 ( P = .005)，获得性耐药机制可能涉及错配修复基因和/或下游组分 TSC2、NF1、NF2、PTEN 和 PIK3CA 的突变。结论 CTO 可以安全地与 TMZ 或放化疗联合治疗 GBM 和间变性胶质瘤，在这个难以治疗的人群中显示出良好的脑渗透和有希望的活动信号。