Cancer chemotherapy and pharmacology

A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma.

PMID 28233053


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 120xa0mg/m(2) intravenously every 3 weeks with dose increases in 60xa0mg/m(2) increments. HT patients were started at 60xa0mg/m(2), with dose increases in 30xa0mg/m(2) increments. The assessment period for dose-limiting toxicity was 1 cycle (21xa0days). In the WT cohort (n = 16), the MTD was 120xa0mg/m(2). In the HT cohort (n = 18), the MTD was 150xa0mg/m(2). 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.

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(S)-(+)-Camptothecin, ≥90% (HPLC), powder