Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma

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• 作者：Thomas Decaens^a ; ^b ; ^c ; ^{thomas.decaens@hmn.aphp.fr} ; Alain Luciani^b ; ^c ; ^d ; Emmanuel Itti^b ; ^c ; ^e ; Anne Hulin^f ; Franç ; oise Roudot-Thoraval^c ; ^g ; Alexis Laurent^b ; ^c ; ^h ; Elie Serge Zafrani^b ; ^c ; ⁱ ; Ariane Mallat^a ; ^b ; ^c ; Christophe Duvoux^a ; ^b ; ^c
• 关键词：Hepatocellular carcinoma ; mTOR inhibitor ; Sirolimus
• 刊名：Digestive and Liver Disease
• 出版年：2012
• 期刊代码：79_15908658
• 类别：med
• 出版时间：July, 2012
• 卷：44
• 期：7
• 页码：610-616
• 文件大小：668 K

摘要

Background

Rapalogs are emerging as promising targeted anticancer drugs. Activation of the PI3K/Akt/mTOR pathway has been observed in 15-50%of hepatocellular carcinomas.

Methods

In this phase II study, patients with advanced hepatocellular carcinoma and underlying cirrhosis received sirolimus (20 mg/week for 1 month then 30 mg/week). Tumour response was assessed every 8 weeks. The primary endpoint was the objective tumour response rate according to the Response Evaluation Criteria in Solid Tumours criteria. Secondary endpoints included the objective response according to the modified Response Evaluation Criteria in Solid Tumours criteria, safety, and pharmacokinetic parameters.

Results

Twenty-five patients received sirolimus for a median of 20.6 weeks. Two patients had an objective response (8%, 95CI: 0.98-26.03), including one complete response, and 8 patients had stable disease. There were 2 cases of grade 5 toxicity (infections) and 5 cases of grade 3 toxicity. The main grade 1/2 toxicity was mild transient fatigue (76%). Median time to radiological progression and overall survival were 15.3 weeks (range: 8.2-173.9) and 26.4 weeks (range: 8.2-173.9) respectively. Use of the modified Response Evaluation Criteria in Solid Tumours criteria did not identify any further responders.

Conclusion

These data suggest that first-line sirolimus shows antitumoural efficacy in advanced hepatocellular carcinoma. Larger trials with Child A patients are needed.