*Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts; †Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ‡Translational Medicine, Exelixis, Inc., South San Francisco, San Francisco, California; §Translational and Experimental Medicine, Sanofi, Vitry-sur-Seine, France; ‖Center for Thoracic Centers, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts; ¶Clinical Development Oncology, Sanofi, Cambridge, Massachusetts; #Pharmacokinetic Modeling and Simulation, Sanofi, Cambridge, Massachusetts; **Biostatistics and Programming, Sanofi, Cambridge, Massachusetts; ††Early Drug Development Center, Dana-Farber Cancer Institute, Boston, Massachusetts; ‡‡Department of Medical Oncology, Vall d'ebron University Hospital, Barcelona, Spain.
J Thorac Oncol. 2014 Mar;9(3):316-23. doi: 10.1097/JTO.0000000000000088.
The primary objectives of this phase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors.
Forty-six patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. Patients were evaluated for adverse events (AEs). Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated protein kinase signaling pathways in tumor and skin samples, and tumor response.
The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. Stable disease was the best overall response reported, occurring in 12 of 32 (37.5%) evaluable patients.
MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction.
本 I 期研究的主要目的是评估 SAR245409（一种泛 I 类磷脂酰肌醇 3-激酶（PI3K）/哺乳动物雷帕霉素靶蛋白抑制剂）联合厄洛替尼治疗晚期实体瘤患者的安全性和最大耐受剂量（MTD）。
共纳入 46 例晚期实体瘤患者。入组患者中肺癌患者（n=37）在研究入组前接受过表皮生长因子受体（EGFR）抑制剂治疗。SAR245409 30、50、70 或 90 mg 每日 1 次（QD）或 20 或 30 mg 每日 2 次（BID）与厄洛替尼 100 mg QD 联合给药，每 28 天为一个周期。SAR245409 的剂量递增采用标准的 3+3 设计。对患者进行不良事件（AE）评估。其他评估包括药代动力学、肿瘤和皮肤样本中 PI3K 和 EGFR/丝裂原活化蛋白激酶信号通路的药效学效应，以及肿瘤反应。
SAR245409 联合厄洛替尼 100 mg QD 的 MTD 分别为 70 mg QD 和 20 mg BID。最常见的治疗相关不良事件（任何级别）为腹泻（35%）、皮疹（35%）和恶心（28%）。无 1 例患者发生 3/4 级以上治疗相关 AE（2.2%）。SAR245409 与厄洛替尼之间未见明显的药代动力学相互作用。在皮肤和肿瘤样本中观察到 PI3K 和 EGFR/丝裂原活化蛋白激酶信号通路生物标志物的抑制。报告的最佳总体缓解为疾病稳定，在 32 例可评估患者中，12 例（37.5%）患者出现疾病稳定。
尽管缺乏主要的药代动力学相互作用，但 SAR245409 联合厄洛替尼的 MTD 低于单药治疗的剂量。
Zotero 插件