Division of Oncology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
Invest New Drugs. 2021 Aug;39(4):1072-1080. doi: 10.1007/s10637-021-01090-w. Epub 2021 Mar 1.
Background Sorafenib (Sor) remains a first-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced efficacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m [n = 6], DL1:Sor 200 mg bid/Evo 480 mg/m [n = 5], DL1a: Sor 200 mg bid/Evo 340 mg/m [n = 7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m. No DLTs were observed at Evo 340 mg/m. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m and Sor 200/Evo 240 mg/m, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%. Conclusions RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC.
索拉非尼（Sor）仍然是肝细胞癌（HCC）或难治性肾细胞癌（RCC）的一线选择。PLC/PRF/5 HCC 模型显示出缺氧的上调，并在索拉非尼与缺氧激活前药依氟鸟苷（Evo）联合使用时增强了疗效。
这项 Ib 期 3+3 设计研究了 3 种 Evo 剂量水平（240、340、480mg/m，第 8、15、22 天），联合索拉非尼 200mg 每日两次口服（po bid，第 1-28 天，28 天周期）。主要目标包括确定索拉非尼+Evo 的最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D）。
18 名患者被纳入（中位年龄 62.5 岁；17 名男性/1 名女性；12 名 HCC/6 名 RCC），分为三个剂量水平（DL0：索拉非尼 200mg bid/Evo 240mg/m [n=6]，DL1：索拉非尼 200mg bid/Evo 480mg/m [n=5]，DL1a：索拉非尼 200mg bid/Evo 340mg/m [n=7]）。报告了两个剂量限制毒性（DLTs），Evo 480mg/m 为 3 级黏膜炎，4 级肝功能衰竭。Evo 240mg/m 时有 1 名患者发生 3 级皮疹 DLT。Evo 340mg/m 时未观察到 DLT。MTD 和 RP2D 分别确定为索拉非尼 200mg/Evo 340mg/m 和索拉非尼 200mg/Evo 240mg/m。最常见的与治疗相关的不良事件包括疲劳、手足综合征、高血压和恶心/呕吐。在 DL0 和 DL1a 各观察到 1 例部分缓解；疾病控制率为 55%。
RP2D 被确定为索拉非尼 200mg bid+Evo 240mg/m。虽然观察到初步的抗肿瘤活性，但未来的发展必须考虑 HCC/RCC 免疫治疗的进展。
