Abstract：
MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose-limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 μg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.
摘要：
MAPK已被报道为犬组织细胞肉瘤的关键致癌途径，可以用曲美替尼进行药理学靶向，MEK1/2的小抑制剂。初步数据在体外和体内模型中显示出有希望的抗肿瘤活性，并代表了将发现从工作台到床边的概念证明。在这个阶段I,使用3+3队列设计的剂量递增研究，曲美替尼在18只癌症犬中进行了评估。根据VCOG-CTCAEv2对不良事件进行分级。收集血液样品和肿瘤活检用于药代动力学和药效学评估。曲美替尼耐受性良好，最大耐受剂量为0.5mg/m2/天，PO.剂量限制性毒性包括全身性高血压，蛋白尿,嗜睡和ALP升高,都是三年级。由于曲美替尼的消除是可饱和的，因此药物暴露随剂量呈线性增加。在500μgQ24h的剂量下（30kg狗中0.5mg/m2/天），大约70%的狗的平均稳态浓度为10ng/mL，大约2周后完成。该阈值与人类的临床疗效相关。在第0天和第7天收集的生物样本中未观察到目标接合。总之,曲美替尼在癌症犬中被认为是安全的，0.5mg/m2/天的剂量是II期研究的推荐剂量。
