A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.
A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.
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DOI：
10.1038/bjc.2016.59
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发表时间：
2016-04-12
影响因子：
8.8
通讯作者：
Schöffski P
中科院分区：
文献类型：
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作者：
Mateo J;Olmos D;Dumez H;Poondru S;Samberg NL;Barr S;Van Tornout JM;Jie F;Sandhu S;Tan DS;Moreno V;LoRusso PM;Kaye SB;Schöffski P
mTOR的激酶活性涉及2个多蛋白复合物（mTORC1-mTORC2）。用rapalogues靶向mTORC1诱导代偿反馈回路，导致AKT/ERK激活，这可能被mTORC2抑制所消除。进行了首次人体试验，评估双重TORC1/TORC2抑制剂osii -027的耐受性、药代动力学和药效学。在三种给药方案（每周连续三天（S1），每周一次（S2）和每日给药（S3））中进行剂量递增，直到确定剂量限制性毒性（DLT）。根据耐受性和药效学开始配对肿瘤活检的扩展队列。128名晚期癌症患者被纳入研究。DLT主要由疲劳、肾功能障碍和心脏事件组成。OSI-027暴露与剂量成正比，Tmax在4小时内，半衰期为~ 14小时。由于S3的MTD总体上被认为是次优的，因此开始了S1和S2的扩展队列。外周血单个核细胞的靶调节从30毫克开始观察，但在肿瘤活检中需要120毫克QD，由于肾毒性，这是一个不可耐受的剂量。无RECIST反应记录，6例（5%）患者病情稳定6个月。在晚期肿瘤患者中，osii -027以剂量依赖的方式抑制mTORC1/2，但在肿瘤活检中，需要高于S1和S3耐受水平的剂量才能产生持续的生物学效应。
The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted. Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics. One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients. OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.