Galunisertib（TGF-β1 受体 I 型抑制剂）联合索拉非尼治疗晚期肝细胞癌的 II 期研究。
A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.
机构信息
University of California, San Francisco, San Francisco, California, USA.
Auckland City Hospital, Grafton, Auckland, New Zealand.
出版信息
Clin Transl Gastroenterol. 2019 Jul;10(7):e00056. doi: 10.14309/ctg.0000000000000056.
INTRODUCTION
Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment.
METHODS
The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK).
RESULTS
Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038).
DISCUSSION
The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.
简介
在肝细胞癌（HCC）的临床前模型中，抑制肿瘤生长因子-β（TGF-β）受体 I 型增强了索拉非尼的活性。Galunisertib 是一种小分子选择性 TGF-β1 受体 I 型抑制剂，在 HCC 的二线治疗的 II 期试验中显示出活性。
方法
在没有先前系统治疗的晚期 HCC 和 Child-Pugh A 肝功能患者中，测试了 galunisertib 和 sorafenib（400 mg BID）的联合用药。Galunisertib 剂量在安全性引导队列中以 80 或 150 mg BID 每天口服给药 14 天，每 28 天一次；在扩展队列中，所有患者均接受 galunisertib 150 mg BID。目标包括肿瘤进展时间、循环甲胎蛋白和 TGF-β1 的变化、安全性、总生存期（OS）、反应率和药代动力学（PK）。
结果
来自 5 个非亚洲国家的 47 名患者入组；3 和 44 名患者分别接受了 80 mg 和 150 mg BID 的 galunisertib 剂量。药代动力学和安全性特征与每种药物的单药治疗一致。对于 150 mg BID galunisertib 队列，中位肿瘤进展时间为 4.1 个月；中位 OS 为 18.8 个月。2 例患者出现部分缓解，21 例患者病情稳定，13 例患者病情进展。TGF-β1 应答者（与基线相比下降>20%）与无应答者的 OS 更长（22.8 与 12.0 个月，P=0.038）。
讨论
Galunisertib 和 sorafenib 的联合用药具有可接受的安全性和延长的 OS 结果。
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