Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany.
Department of Diagnostic & Interventional Radiology, Eberhard Karls University, Tuebingen, Germany.
J Hepatol. 2016 Aug;65(2):280-8. doi: 10.1016/j.jhep.2016.02.043. Epub 2016 Mar 4.
BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib.
Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat.
57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival.
The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications.
No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib.
The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.
目前尚无针对索拉非尼一线治疗后进展的肝细胞癌（HCC）患者的既定治疗方法。本 I/II 期试验研究了组蛋白去乙酰化酶抑制剂瑞米司他联合索拉非尼治疗的安全性、药代动力学和潜在生物标志物。
本探索性、多中心、开放标签、非对照、非随机、平行分组的 I/II 期临床试验纳入了 HCC 患者，这些患者在接受索拉非尼治疗后出现影像学确认的进展。在联合组（n=38）中，四组剂量范围为每日 200 至 600mg 瑞米司他联合 400 至 800mg 索拉非尼。单药组（n=19）接受 600mg 瑞米司他治疗。
57 例患者接受了治疗。最常见的不良事件是胃肠道疾病、血小板减少和疲劳。最大组蛋白去乙酰化酶抑制作用和 H4-乙酰化的最高增加与瑞米司他的 Tmax 相匹配。索拉非尼或 Child-Pugh 评分不影响瑞米司他的典型药代动力学特征。以 6 个治疗周期（12 周，主要终点）后的无进展生存率作为疗效评估指标，瑞米司他组为 12.5%，瑞米司他联合索拉非尼组为 62.5%。瑞米司他组的中位无进展生存期和总生存期分别为 1.8 和 4.1 个月，联合组分别为 6.5 和 8.0 个月。发现血液细胞中锌指蛋白 64（ZFP64）的基线表达与总生存期相关。
在 HCC 患者中，索拉非尼联合瑞米司他的治疗是安全的，并且显示出早期疗效迹象。索拉非尼未改变瑞米司他的药代动力学特征或其体内的组蛋白去乙酰化酶抑制活性。ZFP64 可能对瑞米司他治疗具有预后和潜在预测作用，应在 HCC 以及可能的其他癌症适应证中进一步研究。
目前尚无针对索拉非尼一线治疗后进展的晚期肝细胞癌患者的既定治疗方法。通过抑制组蛋白去乙酰化酶进行表观遗传调节可能能够克服治疗耐药性。这项在接受索拉非尼一线治疗后出现影像学确认进展的患者中进行的探索性 I/II 期临床研究，调查了组蛋白去乙酰化酶抑制剂瑞米司他作为单一药物或与继续应用索拉非尼联合治疗的效果。
该临床试验已在 www.clinicaltrials.gov 上注册，注册号为 NCT00943449。
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