Pan Zhenyu, Yang Guozi, Cui Jiuwei, Li Wei, Li Yu, Gao Pengxiang, Jiang Tongchao, Sun Yanan, Dong Lihua, Song Yuanyuan, Zhao Gang
Department of Radiation-Oncology, The First Hospital of Jilin University, Changchun, China.
Department of Neuro-Oncological Surgery, The First Hospital of Jilin University, Changchun, China.
Front Oncol. 2019 Aug 30;9:838. doi: 10.3389/fonc.2019.00838. eCollection 2019.
We aim to determine the feasibility, safety, maximally tolerated dose (MTD), recommended dose and potential anti-tumor activity of intrathecal pemetrexed (IP). Lung adenocarcinoma patients with recurrent or progressive leptomeningeal metastases (LM) after intrathecal chemotherapy were recruited. IP dose was escalated from 10 mg. A minimum of three patients and a maximum of six were enrolled in each cohort. Schedule protocol was IP twice per week for 2 weeks in induction therapy, followed by once per week for 4 weeks in consolidation therapy. Serial samples of plasma and cerebrospinal fluid (CSF) were obtained for pharmacokinetic studies. Thirteen patients were enrolled between March 2017 and July 2018. driver oncogene was identified in most of the patients. Severe adverse events (AEs) were encountered in 31% (4/13) of the cases, including myelosuppression, radiculitis, and elevation of hepatic aminotransferases (EHA). Study protocol was revised due to lethal myelosuppression. Following protocol revision, vitamin B12 and folic acid supplementation was given at the beginning of treatment, and myelosuppression was well-controlled. Dose-limiting toxicities (DLT) were myelosuppression, radiculitis, and EHA. Two patients (2/2) developed dose-limiting myelosuppression at 15 mg level. One patient (1/6) experienced dose-limiting radiculitis and EHA at 10 mg level. MTD was 10 mg. Response rate was 31% (4/13) and disease control rate was 54% (7/13). The drug concentration showed a decreasing trend in serial CSF samples following each IP. After IP, the peak plasma concentration was reached at 4 h in two cases, 6 h in two cases, 9 h in one case, and 12 h in one case, respectively. Pemetrexed was appropriate for intrathecal administration. IP at 10 mg dose in combination with vitamin supplementation on the schedule of 1-2 times per week showed controllable toxicity and good efficacy. This regimen paves the way for subsequent clinical trial. www.ClinicalTrials.gov, identifier NCT03101579.
我们旨在确定鞘内注射培美曲塞（IP）的可行性、安全性、最大耐受剂量（MTD）、推荐剂量及潜在抗肿瘤活性。招募了在鞘内化疗后出现复发性或进展性软脑膜转移（LM）的肺腺癌患者。IP剂量从10mg开始递增。每个队列至少纳入3名患者，最多纳入6名患者。给药方案为诱导治疗每周鞘内注射IP两次，共2周，随后巩固治疗每周一次，共4周。采集系列血浆和脑脊液（CSF）样本进行药代动力学研究。2017年3月至2018年7月期间共纳入13例患者。大多数患者检测到驱动癌基因。31%（4/13）的病例出现严重不良事件（AE），包括骨髓抑制、神经根炎和肝转氨酶升高（EHA）。由于致死性骨髓抑制，研究方案进行了修订。方案修订后，在治疗开始时给予维生素B12和叶酸补充剂，骨髓抑制得到良好控制。剂量限制性毒性（DLT）为骨髓抑制、神经根炎和EHA。2例患者（2/2）在15mg剂量时出现剂量限制性骨髓抑制。1例患者（1/6）在10mg剂量时出现剂量限制性神经根炎和EHA。MTD为10mg。缓解率为31%（4/13），疾病控制率为54%（7/13）。每次鞘内注射IP后，系列脑脊液样本中的药物浓度呈下降趋势。鞘内注射后，2例患者分别在4小时、2例在6小时、1例在9小时、1例在12小时达到血浆峰值浓度。培美曲塞适合鞘内给药。每周1 - 2次的给药方案中，10mg剂量的IP联合维生素补充剂显示出可控的毒性和良好的疗效。该方案为后续临床试验铺平了道路。ClinicalTrials.gov，标识符NCT03101579。
