Phase 1 Trial and Pharmacokinetic Study of the Oral Platinum Analog Satraplatin in Children and Young Adults With Refractory Solid Tumors Including Brain Tumors
Phase 1 Trial and Pharmacokinetic Study of the Oral Platinum Analog Satraplatin in Children and Young Adults With Refractory Solid Tumors Including Brain Tumors
复制标题
DOI：
10.1002/pbc.25344
复制
发表时间：
2015-04-01
影响因子：
3.2
通讯作者：
Widemann, Brigitte C.
中科院分区：
文献类型：
--
作者：
Akshintala, Srivandana;Marcus, Leigh;Widemann, Brigitte C.
基于成人难治性肿瘤的临床前和临床活性，以及没有明显的神经、肾脏或耳毒性，我们进行了儿科第一阶段试验，以确定口服铂类似物沙特铂对儿童和年轻人难治性实体瘤的毒性、最大耐受量(MTD)和药代动力学。评估毒性、反应、沙特铂药代动力学和特定DNA修复基因的药物基因组表达。结果9名患者接受了1-15个周期(中位数=2)。有2/4的患者在DL2时超过MTD，延迟延长骨髓抑制作为剂量限制性毒性(DLT)。在DL1，0/5的患者有DLTS。常见的非DLT包括骨髓抑制、胃肠道毒性、乏力、头痛、肝酶升高和电解质异常。未观察到明显的神经、肾脏或耳毒性。没有观察到客观反应，但有2名患者经历了延长的病情稳定(6-15个周期)。DL1和DL2的赛特铂暴露(第1天血浆超滤曲线下的面积)相似。结论儿童实体瘤患者口服沙特铂的MTD为60 mg/m(2)/次/天，每28天一次，低于成人推荐剂量80~120 mg/m(2)/次。毒性特征与成人相似，延迟性骨髓抑制为DLT。未观察到明显的神经、肾或耳毒性。儿科血癌2015；62：603-610。(C)2015年威利期刊公司。
BackgroundBased on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors.ProcedureSatraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60mg/m(2)/dose), and DL2 (80mg/m(2)/dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated.ResultsNine patients received 1-15 cycles (median=2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed.ConclusionsThe MTD of oral satraplatin in children with solid tumors was 60mg/m(2)/dose daily x5 days every 28 days, which is lower than the adult recommended dose of 80-120mg/m(2)/dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed. Pediatr Blood Cancer 2015;62:603-610. (c) 2015 Wiley Periodicals, Inc.