Department of Hematology/Oncology, Massachusetts General Hospital, Boston, USA.
Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.
Ann Oncol. 2020 May;31(5):626-633. doi: 10.1016/j.annonc.2020.02.007. Epub 2020 Feb 20.
This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules.
The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels.
In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure.
Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors.
NCT01362374.
这项 Ib 期研究评估了口服 AKT 抑制剂伊帕替薩替布与晚期或转移性实体瘤患者的化疗或激素治疗联合应用的安全性、耐受性、药代动力学和初步疗效，以确定联合剂量限制性毒性（DLTs）、最大耐受剂量以及推荐的 II 期剂量和方案。
该临床研究包括四个联合治疗组：A 组（与多西他赛联合）、B 组[与 mFOLFOX6（改良亚叶酸、5-氟尿嘧啶和奥沙利铂）联合]、C 组（与紫杉醇联合）和 D 组（与恩扎卢胺联合）。主要终点为安全性和耐受性；次要终点为药代动力学、根据实体瘤反应评价标准 1.1 评估的临床活性和前列腺特异性抗原水平。
共纳入 122 例患者。常见不良反应为腹泻、恶心、呕吐、食欲下降和疲劳。联合治疗方案的安全性与背景治疗方案一致，但腹泻、高血糖和皮疹除外，这些反应以前在伊帕替薩替布治疗中观察到过。所有治疗组唯一的联合剂量限制性毒性（DLT）是一例 3 级脱水（伊帕替薩替布 600mg 联合紫杉醇）。伊帕替薩替布的推荐 II 期剂量分别为 600mg（联合 mFOLFOX6）和 400mg（联合紫杉醇）。伊帕替薩替布 600mg 联合多西他赛或恩扎卢胺的最大评估剂量耐受性良好。与恩扎卢胺（细胞色素 P450 3A 诱导剂）联合用药可使伊帕替薩替布的暴露量降低约 50%。
伊帕替薩替布联合化疗或激素治疗具有良好的耐受性，其安全性与 ATP 竞争性 AKT 抑制剂一致。
NCT01362374。
