Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies
Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies
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DOI：
10.1007/s00280-011-1612-1
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发表时间：
2011-12-01
影响因子：
3
通讯作者：
Giaccone, G.
中科院分区：
文献类型：
--
作者：
Schoffski, P.;Dumez, H.;Giaccone, G.
Spisulosine是一种海洋化合物，在临床前研究中显示出抗肿瘤活性。我们报告了一项在晚期实体瘤患者中进行的海洋化合物I期试验的结果，目的是确定每周3小时静脉内（iv.）两个中心共25名患者参加了试验，研究了7个剂量水平，剂量范围为4 - 128 mg/mA（2）/d，未观察到剂量限制性毒性（DLT）。1例患者在200 mg/mA时发生DLT（2），可逆性3级ALT升高。由于螺索罗辛试验项目提前终止，因此未达到MTD，但认为该方案的MTD可能在200 mg/mA（2）范围内。药物相关不良反应包括轻度至中度恶心、发热、注射部位反应和呕吐。在治疗周期4期间观察到1例4级周围运动和感觉神经病变伴全身无力和疼痛，可能导致患者死亡。3级实验室检查异常包括贫血和淋巴细胞减少症以及肝酶（碱性磷酸酶、转氨酶和胆红素）升高。没有观察到客观反应，只有4名患者有短暂的稳定疾病（< 3个月）。PK数据表明，广泛的分布，长的停留时间，和剂量proportionality的agent.Hepato-和神经毒性是时间表独立的剂量限制性不良事件，这种海洋化合物，如本和其他早期临床试验所示。
Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound.Two centers contributed 25 patients to the trial, and 7 dose levels were explored.In dose levels ranging from 4 to 128 mg/mA(2)/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/mA(2), a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/mA(2) for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (< 3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent.Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials.