Temozolomide is a novel oral alkylating agent that has schedule‐dependent clinical activity in human malignant glioma and metastatic melanoma. Little is known about the efficacy of temozolomide in the treatment of canine solid cancers, where broad range of dosages have been used but no maximally tolerated dose (MTD) had been established. The aim of this this open‐label, dose‐escalating study was to determine MTD and dose‐limiting toxicity (DLT) of a single temozolomide cycle in dogs with advanced solid tumours. Temozolomide was administered as a 5‐days course starting at 70 mg/m², using escalation of 10 mg/m² increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing DLT assessed after 1 cycle. Safety evaluation was performed 10 days after dosing. Thirty‐three client‐owned dogs were enrolled. MTD was established at 150 mg/m² and the most frequent adverse events (AEs) were hematologic and hepatic, followed by gastrointestinal, with the majority being self‐resolving and of mild grade. VCOG grade 3 hepatic toxicity and grade 4 thrombocytopenia were defined as DLTs at 160 mg/m². A subcohort of dogs received multiple temozolomide doses on a 4‐week cycle and no cumulative toxicity was documented. Conclusions of this study define temozolomide MTD at 150 mg/m² when given once daily over 5 days. Future trials on the efficacy of temozolomide administered at its MTD are warranted.

中文翻译：

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一项开放标签剂量递增研究，评估了替莫唑胺单次 5 天疗程在患有晚期癌症的犬中的耐受性和安全性。

替莫唑胺是一种新型口服烷化剂，在人类恶性胶质瘤和转移性黑色素瘤中具有时间表依赖性临床活性。关于替莫唑胺治疗犬实体癌的疗效知之甚少，其中已使用了广泛的剂量范围，但尚未确定最大耐受剂量 (MTD)。这项开放标签、剂量递增研究的目的是确定单个替莫唑胺周期对晚期实体瘤犬的 MTD 和剂量限制性毒性 (DLT)。替莫唑胺从 70 mg / m ²开始作为 5 天疗程给药，使用 10 mg / m ²递增每个剂量水平增加 3 只狗。MTD 是根据 1 个周期后评估的经历 DLT 的狗的数量建立的。在给药后 10 天进行安全性评估。登记了 33 只客户拥有的狗。MTD 设定为 150 mg / m ²，最常见的不良事件 (AE) 是血液学和肝脏，其次是胃肠道，大多数是可自行解决的轻度不良事件。VCOG 3 级肝毒性和 4 级血小板减少症定义为 160 mg/m ^{2 的}DLT 。一组狗以 4 周为周期接受多次替莫唑胺剂量，没有记录到累积毒性。本研究的结论将替莫唑胺 MTD 定义为 150 mg / m ²每天给药一次超过 5 天。未来有必要对替莫唑胺在其 MTD 时的疗效进行试验。