Phase I study of the combination of temsirolimus and pazopanib in advanced solid tumors.
Phase I study of the combination of temsirolimus and pazopanib in advanced solid tumors.
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DOI：
10.1097/cad.0b013e3283618b7b
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发表时间：
2013-07
影响因子：
2.3
通讯作者：
Lara PN Jr
中科院分区：
文献类型：
--
作者：
Semrad TJ;Eddings C;Dutia MP;Christensen S;Lara PN Jr
抑制血管内皮生长因子受体（VEGFR）或哺乳动物雷帕霉素靶蛋白（mTOR）信号传导可改善几种晚期实体瘤患者的预后。我们进行了坦罗莫司与帕唑帕尼的I期试验，以研究同时“垂直抑制”VEGFR和mTOR通路的可行性。晚期实体瘤患者，既往无帕唑帕尼或mTOR抑制剂，体能状态良好，终末器官功能可接受。在典型的3 + 3递增设计中，从替西罗莫司15 mg每周静脉（IV）输注和帕唑帕尼400 mg每日口服开始，我们将剂量限制性毒性（DLT）定义为前28天周期内可归因的3级或更高非血液学不良事件，最大耐受剂量定义为少于2例患者发生DLT的最大剂量水平。在初始剂量水平下，2例患者发生4例DLT（厌食、疲乏、低钠血症、低磷血症）。在减少至替西罗莫司10 mg IV每周一次和帕唑帕尼200 mg口服每日一次后，3例患者中有1例发生DLT（疲劳），随后扩展的第一例患者发生剂量限制性低磷血症。超过1例患者发生的3级或3级以上不良事件包括白细胞减少症、中性粒细胞减少症、疲乏和低磷血症。7例可评价患者中有4例的最佳缓解为肿瘤缩小，但不符合RECIST部分缓解标准。由于体质和电解质紊乱，在该人群中以具有临床意义的剂量联合坦罗莫司和帕唑帕尼是不可行的。
Inhibition of either vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin (mTOR) signaling improves outcomes in patients with several advanced solid tumors. We conducted a phase I trial of temsirolimus with pazopanib to investigate the feasibility of simultaneous “vertical inhibition” of VEGFR and mTOR pathways. Patients with advanced solid tumors, no prior pazopanib or mTOR inhibitor, good performance status and acceptable end-organ function were eligible. In a typical 3 + 3 escalation design starting at temsirolimus 15 mg by intravenous (IV) infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher non-hematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than 2 patients experienced DLT. At the initial dose level, 2 patients had 4 DLTs (anorexia, fatigue, hyponatremia, hypophosphatemia). After reduction to temsirolimus 10 mg IV weekly and pazopanib 200 mg orally daily, 1 of 3 patients had DLT (fatigue) and the first patient in the subsequent expansion had dose-limiting hypophosphatemia. Attributable grade 3 or higher adverse events in more than one patient included leukopenia, neutropenia, fatigue, and hypophosphatemia. Tumor reduction not meeting RECIST criteria for partial response was the best response in 4 of 7 evaluable patients. The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population due to constitutional and electrolyte disturbances.