Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors
Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors
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DOI：
10.1007/s10637-011-9772-8
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发表时间：
2012-12-01
影响因子：
3.4
通讯作者：
Soria, J. C.
中科院分区：
文献类型：
--
作者：
Massard, C.;Salazar, R.;Soria, J. C.
ES-285 （spisulosin）是一种从海洋软体动物Spisula多项式中提取的新型化合物，具有临床前抗肿瘤活性。该I期临床试验旨在确定ES-285在晚期实体瘤患者中的最大耐受剂量（MTD）和推荐剂量（RD），并评估ES-285的安全性、药代动力学和初步疗效数据。患者与方法对两所医疗机构的61例患者进行ES-285每3周静脉滴注3 h的治疗。评估了9个剂量水平。结果4 ~ 128 mg/m剂量递增过程中未观察到剂量限制性毒性（dlt）(2)。六名患者有七种dlt，测试的三种最高剂量水平：256 mg/m(2) (n = 2), 200 mg/m(2) （n = 3）和160 mg/m(2) （n = 1）。3/4级转氨酶升高（n = 3）， 3/4级中枢神经系统障碍[精神错乱（n = 2）和共济失调（n = 1）]， 3级发热（n = 1）是ES-285给药方案的剂量限制性毒性。药动学分析表明，ES-285剂量呈线性，分布广，半衰期长。在一名接受ES-285 128 mg/m治疗的转移性黑色素瘤患者中观察到一种未证实的部分缓解，18名患者在不同剂量水平下表现出稳定的疾病，其中6名患者持续时间超过3个月。结论剂量水平VIII （200 mg/m(2)）为MTD，剂量水平IX （160 mg/m(2)）为RD，抗肿瘤活性有限。
Background ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors. Patients and Methods Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated. Results No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m(2). Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m(2) (n = 2), 200 mg/m(2) (n = 3) and 160 mg/m(2) (n = 1). Grade 3/4 transaminase increases (n = 3), grade 3/4 central nervous system disorders [confusion (n = 2) and ataxia (n = 1)], and grade 3 pyrexia (n = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m(2), and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients. Conclusion Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed.