A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma
A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma
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DOI：
10.1016/j.ejca.2012.11.008
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发表时间：
2013-03-01
影响因子：
8.4
通讯作者：
Toh, H. C.
中科院分区：
文献类型：
--
作者：
Choo, S. P.;Chowbay, B.;Toh, H. C.
背景与目的：临床前研究表明，雷帕霉素联合贝伐单抗治疗肝癌具有叠加效应。我们进行了一项1期研究，以评估该联合疗法在肝癌患者中的安全性和药代动力学。方法：成年晚期肝癌患者接受静脉注射贝伐单抗（5mg /kg / 14天）和口服雷帕霉素（1- 6mg /天；3 + 3剂量递增设计）。计算机断层扫描评估肿瘤反应和治疗安全性。药代动力学评估确定了雷帕霉素给药前后的血药浓度。动态增强计算机断层扫描分析肿瘤区域的血流、通透性表面积积、血管内血容量和细胞外-血管外体积。结果：24例患者得到治疗。雷帕霉素5mg有两种剂量限制性毒性：3级血小板减少症和3级粘膜炎。雷帕霉素的最大耐受剂量为4mg。不良事件（1-2级）包括高血糖（83%）、血小板减少（75%）、疲劳（46%）、粘膜炎（46%）、厌食症（42%）、腹泻（33%）和蛋白尿（12.5%）。在20名可评估的参与者中，1人达到完全缓解，持续4.5个月，2人达到部分缓解，14人达到疾病稳定，3人病情进展。中位总生存期为9.4个月；无进展生存期为5.5个月。雷帕霉素0 ~无穷小时浓度时间曲线下的剂量水平和稳态面积与血流速率和透性表面积变化呈负相关。治疗22天后，血流量、通透表面积和细胞内血容量较基线显著降低。结论：推荐的2期剂量为4mg雷帕霉素联合贝伐单抗。观察到抗血管活性的证据以及有希望的临床活性。(C) 2012 Elsevier Ltd.版权所有。
Background & Aims: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma.Methods: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5 mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3 + 3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume.Results: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5 mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%).Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months.Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume.Conclusions: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity. (C) 2012 Elsevier Ltd. All rights reserved.