UCLA Division of Hematology/Oncology, Los Angeles, CA 90404, USA.
Clin Cancer Res. 2011 Dec 15;17(24):7754-64. doi: 10.1158/1078-0432.CCR-11-1002. Epub 2011 Oct 5.
Tivantinib, an oral, non-ATP competitive, selective c-MET inhibitor, exhibited antitumor activity in preclinical models. This open-label, phase I, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of tivantinib in patients with advanced or metastatic solid tumors refractory to standard therapy.
Thirteen dose levels of tivantinib ranging from 10 to 360 mg twice a day were administered to patient cohorts in 21-day cycles (14 days on/7 days off); three active pharmaceutical ingredient forms of tivantinib (amorphous, crystalline A, and crystalline B) were also investigated. Treatment was continued until the occurrence of unacceptable toxicity, tumor progression, patient withdrawal, or death.
A total of 79 patients with advanced solid tumors were enrolled. A maximum tolerated dose was not determined. Tivantinib was well tolerated, with mild to moderate toxicities. Two patients discontinued the study drug due to treatment-emergent adverse events. Dose-limiting grade of 3 or more toxicities including leukopenia, neutropenia, thrombocytopenia, vomiting, and dehydration, were observed in 2 patients treated with tivantinib 360 mg twice a day. The rate of absorption of tivantinib peaked approximately 2 to 4 hours after initial dosing, followed by a linear decrease in plasma concentrations. Increases in tivantinib exposure were not dose proportional. There was significant interpatient pharmacokinetic variability; however the clinical safety of tivantinib seemed unaffected. Three patients (3.8%) achieved a partial response and 40 patients (50.6%) maintained stable disease for a median of 19.9 weeks.
Tivantinib 360 mg twice a day was well tolerated in patients with refractory advanced solid tumors. The results of this trial warrant further clinical investigation. Clin Cancer Res; 17(24); 7754-64. ©2011 AACR.
替沃扎尼布（Tivantinib）是一种口服、非三磷酸腺苷竞争性、选择性 c-MET 抑制剂，在临床前模型中表现出抗肿瘤活性。这项开放标签、I 期、剂量递增研究评估了替沃扎尼布在标准治疗耐药的晚期或转移性实体瘤患者中的安全性、耐受性、药代动力学和药效学。
替沃扎尼布的 13 个剂量水平（10-360mg，每日两次）在 21 天的周期内（14 天给药/7 天停药）用于患者队列；还研究了替沃扎尼布的三种原料药形式（无定形、结晶 A 和结晶 B）。治疗继续进行，直到出现不可接受的毒性、肿瘤进展、患者退出或死亡。
共纳入 79 名晚期实体瘤患者。未确定最大耐受剂量。替沃扎尼布具有良好的耐受性，毒性为轻度至中度。两名患者因治疗相关不良事件而停止研究药物。两名接受替沃扎尼布 360mg 每日两次治疗的患者出现剂量限制的 3 级或更高级别的毒性，包括白细胞减少、中性粒细胞减少、血小板减少、呕吐和脱水。替沃扎尼布的吸收速率在初始给药后约 2 至 4 小时达到峰值，随后血浆浓度呈线性下降。替沃扎尼布的暴露量增加与剂量不成比例。患者间药代动力学变异性很大；然而，替沃扎尼布的临床安全性似乎未受影响。三名患者（3.8%）获得部分缓解，40 名患者（50.6%）的疾病稳定时间中位数为 19.9 周。
替沃扎尼布 360mg 每日两次在耐药性晚期实体瘤患者中耐受良好。这项试验的结果值得进一步的临床研究。临床癌症研究；17（24）；7754-64。©2011AACR。
