阿帕替尼一线治疗晚期肝细胞癌的前瞻性、随机、开放、全国多中心Ⅱ期临床试验

摘要

目的 观察、确定不同剂量甲磺酸阿帕替尼治疗晚期肝细胞癌(HCC)的有效性和安全性.方法 设计和开展一项前瞻性、随机、开放、两剂量组、多中心的Ⅱ期临床试验.2010年6月至2013年7月全国16家研究中心共纳入121例未接受系统治疗(包括分子靶向药物和系统化疗)的晚期HCC受试者.第1阶段入组104例,按1∶1随机分配,分别接受口服阿帕替尼750 mg qd(n=51)和850 mg qd(n=53)治疗;第2阶段,为了进一步探索高剂量(850 mg qd)的安全性,继续纳入850mg剂量组17例,即850 mg队列的总样本量扩大至70例.主要研究终点为疾病进展时间(TTP),次要研究终点为总生存时间(0S)、客观缓解率(ORR)、疾病控制率(DCR)以及安全性指标,采用RECIST 1.1版和NCI CTC 4.03版分别评价客观疗效和不良事件.结果 750 mg剂量组和850 mg剂量组的中位TTP分别为3.32个月(95％CI:2.04～5.86个月)和4.21个月(95％CI:2.14～5.86个月),中位OS分别为9.82个月(95％CI:5.71～12.07个月)和9.71个月(95％CI:6.61～ 12.04个月),ORR分别为2.0％和10.0％,DCR分别为64.7％和58.6％;上述各项指标的组间差异均无统计学意义(P＞0.05).750 mg剂量组和850 mg剂量组3级及以上药物相关不良事件的发生率分别为58.8％和58.6％(P＞0.05);没有发生非预期的不良事件.结论 阿帕替尼可以用于治疗晚期HCC,750 mg qd和850 mg qd的有效性和安全性基本一致,耐受性较好.因此,推荐口服阿帕替尼750 mg qd作为Ⅲ期临床研究的给药方法和剂量.%Objective To observe and assess the efficacy and safety of different dosages of.apatinib mesylate on advanced hepatocellular carcinoma(HCC).Methods It was a prospective,randomised,open-labeled,two dosages,national multicentre,and phase Ⅱ clinical trial.From June 2010 to July 2013,a total of 121 advanced HCC patients who had not received any systemic treatment(including molecular targeted therapy and systemic chemotherapy) were enrolled from 16 centers in China.First,104 patients were randomly allocated in a 1 ∶ 1 ratio to two cohorts to receive oral apatinib at an initial dosage of 750 mg qd (n =51) or 850 mg qd (n =53).To further explore the safety of high dosage(850 mg qd),17 patients were recruited to receive apatinib 850 mg qd,thus the sample of 850 mg cohort was expanded to 70 cases.The primary endpoint was median time to progression(TTP),and the secondary endpoints included overall survival (OS),objective response rate (ORR),disease control rate (DCR) and adverse events (AEs).Tumor response and AEs were evaluated according to RECIST 1.1 criteria and NCI CTC 4.0 criteria respectively.Results The TTP of patients treated with 750 mg and 850 mg apatinib were 3.32 months (95％CI:2.04-5.86 months) and 4.21 months(95％ CI:2.14-5.86 months),and the median OS were 9.82 months(95％CI:5.71-12.07 months) and 9.71 months(95％CI:6.61-12.04 months),respectively.ORR was 2.0％ and 10.0％,and DCR were 64.7％ and 58.6％,respectively.No statistical differences in the above efficacy indexes were found between the two dosages(P＞0.05).The drug-related AEs of grade ≥3 occurred in 58.8％ and 58.6％ patients receiving 750 mg and 850 mg apatinib(P＞0.05),respectively.No unexpected AEs occurred.Conclusion Apatinib can be used for advanced HCC.Apatinib at an initial dosage of 750 mg or 850 mg qd orally has equal efficacy and safety in advanced HCC patients with good tolerance.Hence,oral administration ofapatinib 750 mg qd is recommended for the further phase Ⅲ clinical trial.