Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C β-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer
Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C β-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer
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DOI：
10.1158/1078-0432.ccr-06-2912
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发表时间：
2007-08-01
影响因子：
11.5
通讯作者：
Voest, Emile E.
中科院分区：
文献类型：
--
作者：
Rademaker-Lakhai, Jeany M.;Beerepoot, Laurens V.;Voest, Emile E.
目的：以蛋白激酶C和磷脂酰肌醇3-激酶/AKT信号转导通路为靶点，减少肿瘤血管生成和细胞增殖，诱导细胞死亡。试验设计：晚期癌症患者口服恩扎他林14天，然后每日服药21天，吉西他滨每天1次，吉西他滨每天8天，顺铂每天2次，剂量从每天350 mg增加到每天2次，吉西他滨剂量为1,000或1,250 mg/m(2)，顺铂2剂量为60或75 mg/m(2)。循环包被细胞数和CD146和CD133的mRNA表达被评估为药效学标志。结果：33例患者(中位年龄，2岁)58岁)参加了7个剂量水平的研究。最大耐受量尚未确定。报告了两种剂量限制性毒性(经心率延长校正的2级QT间期和3级疲劳)。其他不良反应包括3/4级中性粒细胞减少症(3/6例)、血小板减少症(1例/6例)、3级白细胞减少症(2例)和乏力(5例)。每日两次(250毫克)的硫代巴比妥林可导致更多的停药和低毒反应。在联合用药中，苯扎托林的暴露略有减少，但仍高于1400nmol/L的目标，而吉西他滨/顺铂的暴露没有改变。3例(9.1%)部分缓解，13例(39.4%)病情稳定。循环内皮细胞数量和CD146、CD133基因表达的检测并不有助于剂量递增的决策。结论：推荐的11期剂量为：1次/d，1,250 mg/m(2)吉西他滨，75 mg/m(2)顺铂。该方案耐受性良好，任何药物的药代动力学变量均无明显变化。
Purpose: Enzastaurin targets the protein kinase C and phosphaticlylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin.Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m(2) and cisplatin 2 doses were either 60 or 75 mg/m(2).Circulating enclothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers.Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily ( >= 250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1 %) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation.Conclusions: Recommended phase 11 dose is 500 mg enzastaurin once daily, 1,250 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.