Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Betta Pharmaceutical Co., Ltd., Hangzhou 301106, China.
EBioMedicine. 2020 May;55:102755. doi: 10.1016/j.ebiom.2020.102755. Epub 2020 Apr 23.
Vorolanib (X-82, CM082) is a multi-target tyrosine kinase inhibitor. This study aimed to evaluate the tolerability, safety, pharmacokinetics and antitumor activities of vorolanib plus everolimus (an inhibitor of mammalian target of rapamycin).
Patients had histologically or cytologically confirmed advanced RCC and failed with standard therapy were eligible for this study. Dose-escalated combinations of vorolanib (100, 150 or 200 mg once daily) with everolimus (5 mg once daily) were administered on 28-day cycles until disease progression or unacceptable toxicity using a conventional 3 + 3 dose-escalation design.
22 patients (100 mg n = 4, 150 mg n = 3, 200 mg n = 15) were enrolled. Only one patient experienced dose-limiting toxicity (DLT, grade 4 thrombocytopenia) in the vorolanib 200 mg combination cohort, and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events were proteinuria (100%), leukopenia (77%), hypercholesterolaemia (77%), increased low-density lipoprotein (68%), hypertriglyceridaemia (64%), hyperglycaemia (59%), and fatigue (55%). Most treatment-related adverse events were grade 1 to 2, with grade 3 or higher toxicities mostly seen in the 200 mg cohort. Single dosing of vorolanib demonstrated dose-proportional increases in the C and AUC, and observed short t ranging from 4.74±1.44 to 12.89±7.49 h. The pharmacokinetic parameters for everolimus were similar among all cohorts. Of 19 evaluable patients, the ORR and DCR was 32% (n = 6, 95% CI, 13-57%) and 100% (95% CI, 82-100%), respectively.
Combination therapy of vorolanib 200 mg plus everolimus 5 mg once daily is potentially effective with potential activity. Further evaluation of the combination in advanced RCC patients is ongoing (NCT03095040).
Betta Pharmaceutical Co., Ltd., Hangzhou, China.
Vorolanib（X-82，CM082）是一种多靶点酪氨酸激酶抑制剂。本研究旨在评估vorolanib 联合依维莫司（一种哺乳动物雷帕霉素靶蛋白抑制剂）的耐受性、安全性、药代动力学和抗肿瘤活性。
本研究纳入了组织学或细胞学证实的晚期 RCC 患者，且这些患者经标准治疗失败。采用传统的 3+3 剂量递增设计，在 28 天的周期内给予递增剂量的 vorolanib（100、150 或 200mg，每日一次）联合依维莫司（5mg，每日一次）。
共纳入 22 例患者（vorolanib 100mg 组 n=4，150mg 组 n=3，200mg 组 n=15）。在 vorolanib 200mg 联合组中，仅 1 例患者发生剂量限制性毒性（DLT，4 级血小板减少症），未达到最大耐受剂量（MTD）。最常见的治疗相关不良事件是蛋白尿（100%）、白细胞减少症（77%）、高胆固醇血症（77%）、低密度脂蛋白升高（68%）、高甘油三酯血症（64%）、高血糖症（59%）和疲劳（55%）。大多数治疗相关不良事件为 1-2 级，3 级或更高毒性主要见于 200mg 组。单次给予 vorolanib 可使 C 和 AUC 呈剂量依赖性增加，观察到的 t 较短，范围为 4.74±1.44 至 12.89±7.49h。所有队列中，everolimus 的药代动力学参数相似。在 19 例可评估患者中，客观缓解率和疾病控制率分别为 32%（n=6，95%CI，13-57%）和 100%（95%CI，82-100%）。
vorolanib 200mg 联合 everolimus 5mg 每日一次的联合治疗具有潜在疗效。目前正在对晚期 RCC 患者进行该联合治疗的进一步评估（NCT03095040）。
杭州贝达药业股份有限公司，中国。
