Phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine.
Phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine.
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DOI：
10.1111/cas.13086
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Esumi H
中科院分区：
文献类型：
--
作者：
Ikeda M;Sato A;Mochizuki N;Toyosaki K;Miyoshi C;Fujioka R;Mitsunaga S;Ohno I;Hashimoto Y;Takahashi H;Hasegawa H;Nomura S;Takahashi R;Yomoda S;Tsuchihara K;Kishino S;Esumi H
GBS-01，牛蒡果实提取物。是一种富含牛蒡子苷元的口服药物，据报道其通过减弱癌细胞对葡萄糖剥夺的耐受性而发挥抗肿瘤活性。我们基于吉西他滨难治性晚期胰腺癌患者的剂量限制性毒性（DLT）频率和药代动力学研究了GBS-01的最大耐受剂量。GBS-01以递增剂量口服给药，剂量从3.0 g（含1.0 g牛蒡果提取物）至12.0 g q.d. DLT定义为治疗前28天内出现的4级血液学毒性和3级或4级非血液学毒性。入组了15例患者（GBS-01剂量水平1 [3.0 g]，3例患者;剂量水平2 [7.5 g]，3例患者;剂量水平3 [12.0 g]，9例患者）。三个剂量水平中的任何一个剂量水平的患者均未显示任何DLT体征。主要不良事件为血清γ-谷氨酰转肽酶升高、高血糖症和血清总胆红素升高;然而，所有毒性均为轻度。在15例患者中，1例显示确认的部分缓解，4例患者病情稳定。患者的中位无进展生存期和总生存期分别为1.1和5.7个月。药代动力学研究表明，牛蒡子苷元的生物利用度高，并且该药物与葡萄糖醛酸快速结合。GBS-01的推荐剂量为12.0 g q.d，获得了良好的临床反应。本试验在UMIN-CTR（http：//www.umin.ac.jp/ctr/index-j.htm）注册，识别号为UMIN 000005787。
GBS‐01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS‐01 based on the frequency of the dose‐limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS‐01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non‐hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS‐01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ‐glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression‐free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS‐01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN‐CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number UMIN000005787.
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