Clarke Jennifer L, Molinaro Annette M, Cabrera Juan R, DeSilva Ashley A, Rabbitt Jane E, Prey Joshua, Drummond Daryl C, Kim Jaeyeon, Noble Charles, Fitzgerald Jonathan B, Chang Susan M, Butowski Nicholas A, Taylor Jennie W, Park John W, Prados Michael D
Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
Department of Neurology, University of California, San Francisco, 400 Parnassus Avenue, San Francisco, CA, 94122, USA.
Cancer Chemother Pharmacol. 2017 Mar;79(3):603-610. doi: 10.1007/s00280-017-3247-3. Epub 2017 Feb 23.
Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, irinotecan liposome injection (nal-IRI) results in prolongation of drug exposure and higher tissue levels of drug due to slower metabolism and the effect of enhanced permeability and retention. The objective of the current study was to assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent high-grade glioma stratified based on UGT1A1 genotyping.
This phase I study stratified patients with recurrent high-grade glioma into 2 groups by UGT1A1 status: homozygous WT ("WT") vs heterozygous WT/*28 ("HT"). Patients who were homozygous *28 were ineligible. The design was a standard 3 + 3 phase I design. WT patients were started at 120 mg/m intravenously every 3 weeks with dose increases in 60 mg/m increments. HT patients were started at 60 mg/m, with dose increases in 30 mg/m increments. The assessment period for dose-limiting toxicity was 1 cycle (21 days).
In the WT cohort (n = 16), the MTD was 120 mg/m. In the HT cohort (n = 18), the MTD was 150 mg/m. Dose-limiting toxicity in both cohorts included diarrhea, some with associated dehydration and/or fatigue. PK results were comparable to those seen in other PK studies of nal-IRI; UGT1A1*28 genotype (WT vs. HT) did not affect PK parameters.
Nal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.
伊立替康在胶质瘤模型中已显示出临床前活性，但临床研究中仅观察到适度疗效，这可能与药物分布和/或药代动力学限制有关。在临床前测试中，伊立替康脂质体注射剂（nal-IRI）由于代谢较慢以及增强的渗透和滞留效应，导致药物暴露时间延长和组织药物水平升高。本研究的目的是评估nal-IRI的安全性和药代动力学（PK），并确定根据UGT1A1基因分型分层的复发性高级别胶质瘤患者的最大耐受剂量（MTD）。
本I期研究根据UGT1A1状态将复发性高级别胶质瘤患者分为2组：纯合野生型（“WT”）与杂合野生型/28（“HT”）。纯合28的患者不符合条件。设计为标准的3+3 I期设计。WT患者每3周静脉注射120mg/m²开始，剂量以60mg/m²递增。HT患者从60mg/m²开始，剂量以30mg/m²递增。剂量限制毒性的评估期为1个周期（21天）。
在WT队列（n = 16）中，MTD为120mg/m²。在HT队列（n = 18）中，MTD为150mg/m²。两个队列中的剂量限制毒性均包括腹泻，部分伴有脱水和/或疲劳。PK结果与nal-IRI的其他PK研究结果相当；UGT1A1*28基因型（WT与HT）不影响PK参数。
静脉注射nal-IRI时没有出现意外毒性。值得注意的是，UGT1A1基因型与毒性无关，也不影响PK谱。
