First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors
First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors
复制标题
DOI：
10.1158/1078-0432.ccr-12-3404
复制
发表时间：
2013-07-01
影响因子：
11.5
通讯作者：
Banerji, Udai
中科院分区：
文献类型：
--
作者：
Sessa, Cristiana;Shapiro, Geoffrey I.;Banerji, Udai
目的：进行了一项I期研究，主要目的是确定晚期实体瘤患者中AUY 922的最大耐受剂量（MTD）。次要目标包括安全性，药代动力学和药效学的特征。患者和方法：晚期实体瘤患者接受1小时静脉注射AUY 922每周一次，在28天的周期。一个自适应贝叶斯逻辑回归模型，采用观察到的剂量限制性毒性（DLT）在第一个治疗周期被用来指导剂量递增的决定，与确定的MTD被用于在II期研究。结果：101例患者入组，并探讨剂量范围为2至70毫克/平方米（2）。8例患者（22-70 mg/m2）发生DLT，包括腹泻、虚弱/疲劳、厌食、房扑和视觉症状。在70 mg/m2时，AUY 922达到的浓度与一系列异种移植模型中的活性浓度一致。有证据表明外周血单核细胞（HSP 70诱导）和肿瘤（客户蛋白消耗和F-18-FDG PET代谢活性降低）中存在靶向抑制。根据毒性、药代动力学和药效学特征，建议II期推荐剂量（RP 2D）为70 mg/m2。结论：在RP 2D为70 mg/m2时，AUY 922表现出可接受的耐受性，并且已经在HER 2阳性乳腺癌、胃癌和非小细胞肺癌患者中启动了II期单药和联合用药研究。临床癌症研究; 19（13）; 3671-80。（C）2013年AACR。
Purpose: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles.Patients and Methods: Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) in the first treatment cycle was used to guide dose-escalation decisions, with the established MTD to be used in phase II studies.Results: One hundred and one patients were enrolled and explored at doses in the range of 2 to 70mg/m(2). DLTs occurred in 8 patients (22-70 mg/m(2)) and included diarrhea, asthenia/fatigue, anorexia, atrial flutter, and visual symptoms. At 70 mg/m(2), the AUY922 concentration achieved was consistent with active concentrations in a range of xenograft models. There was evidence of target inhibition in peripheral blood mononuclear cells (HSP70 induction) and tumor (client protein depletion and reduction of metabolic activity by F-18-FDG PET). The recommended phase II dose (RP2D) of 70mg/m(2) was proposed on the basis of toxicity and pharmacokinetic and pharmacodynamic profiles.Conclusions: At the RP2D of 70 mg/m(2), AUY922 exhibited acceptable tolerability, and phase II single-agent and combination studies have been initiated in patients with HER2-positive breast, gastric, and non-small cell lung cancers. Clin Cancer Res; 19(13); 3671-80. (C)2013 AACR.