ASCO2013：国立台湾大学Ann-Lii Cheng将开展Regorafenib治疗进展期肝细胞癌3期试验

背景： 索拉非尼用于HCC一线全身性治疗已被广为接受，但对于接受索拉非尼治疗后进展期患者目前尚无标准的治疗选择。一项开放标签2期研究提示多激酶抑制剂REG具有可接受的安全性能，且显示出对于进展期HCC患者的抗癌活性的证据(Bolondi et al. Eur J Cancer 2011; 47 [Suppl 1]: abstract 6.576)：病例对照设置为26/36例患者(72%)，中位肿瘤进展时间（TTP）为4.3月，中位总体生存时间为13.8个月。基于这一颇有前景的数据，研究者将开展3期试验。
方法：该项随机、双盲、安慰剂(PBO)对照、多国参与的研究(ClinicalTrials.gov identifier NCT01774344)将对REG vs PBO治疗接受索拉非尼后进展期HCC患者的有效性和耐受性进行评估（目标n=530）。入组标准包括巴塞罗那临床肝癌阶段B或C，Child-Pugh肝功能分级A、东部肿瘤协作组的性能状态（ECOG PS）评分0或1.。
入组前超过8周中止索拉非尼治疗或接受其他针对HCC的全身性治疗的患者被排除。患者按2：1比例随机分组，分别接受REG 160 mg或与之匹配的PBO OD，每循环4周，治疗1——3周；所有患者均接受最优支持治疗。治疗持续至疾病进展、患者死亡、不能耐受毒性、或患者/研究者决策停止治疗。研究药物可能被推迟或减量应用，以控制临床出现的明显药物相关的毒性作用。试验主要终点为OS，次要终点为TTP，无进展生存，肿瘤应答，以及安全性。
根据随机化分组进行分析，按地理区域（亚洲VS 其他地区），ECOG PS (0 vs 1)，alfa-甲胎蛋白水平(<400 vs ≥400 ng/ml)，肝外疾病（是或否），以及大血管侵犯（是或否）进行分层。此外，利用血液，血浆，以及存档组织等标本进行药物代谢动力学和生物标志物分析，以及健康相关的生活质量，并对卫生服务利用予以检测。Clinical trial information: NCT01774344。
Regorafenib (REG) in patients with hepatocellular carcinoma (HCC) progressing following sorafenib: An ongoing randomized, double-blind, phase III trial.
Abstract
Background: Sorafenib is the accepted first-line systemic therapy for HCC, but no standard option is available for patients with tumor progression following sorafenib. An open-label phase II study suggested that REG, a multikinase inhibitor, had an acceptable safety profile and showed evidence of antitumor activity in patients with progressive HCC (Bolondi et al. Eur J Cancer 2011; 47 [Suppl 1]: abstract 6.576): disease control was achieved in 26/36 patients (72%) and median time to progression (TTP) was 4.3 months; median overall survival (OS) was 13.8 months. On the basis of these promising data, a phase III trial was designed. Methods: This randomized, double-blind, placebo (PBO)-controlled, multinational study (ClinicalTrials.gov identifier NCT01774344) will assess the efficacy and tolerability of REG vs PBO in patients with HCC that has progressed following sorafenib treatment (target n=530). Inclusion criteria include Barcelona Clinic Liver Cancer stage B or C disease, Child–Pugh A liver function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Patients who discontinued sorafenib ≥8 weeks before study entry or who received other previous systemic therapy for HCC will be excluded. Patients will be randomized in a 2:1 ratio to receive REG 160 mg or matching PBO OD for weeks 1–3 of each 4-week cycle; all patients will also receive best supportive care. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. The primary endpoint is OS; secondary endpoints are TTP, progression-free survival, tumor response, and safety. Analysis will be according to randomized group, stratified by geographic region (Asia vs rest of world), ECOG PS (0 vs 1), alfa-fetoprotein level (<400 vs ≥400 ng/ml), extrahepatic disease (yes vs no), and macrovascular invasion (yes vs no). In addition, blood, plasma, and archival tissue will be assessed for pharmacokinetic and biomarker analyses, and health-related quality of life and health utility will be measured. Clinical trial information: NCT01774344.