A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma
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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/m2 intravenously every 3 weeks with dose increases in 60 mg/m2 increments. HT patients were started at 60 mg/m2, with dose increases in 30 mg/m2 increments. The assessment period for dose-limiting toxicity was 1 cycle (21 days).
In the WT cohort (n = 16), the MTD was 120 mg/m2. In the HT cohort (n = 18), the MTD was 150 mg/m2. 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.
KeywordsGlioblastoma High-grade glioma Chemotherapy Irinotecan Liposomes
The authors would like to thank Ms. Ilona Garner (UCSF) for her expert assistance with manuscript preparation and editing.
Compliance with Ethical Standards
This clinical trial was funded by the UCSF Brain Tumor Research Center’s Specialized Program of Research Excellence (SPORE) Grant from the NCI: P50 CA097257.
Conflict of interest
Daryl C. Drummond is both an employee and stockholder in Merrimack, and is the inventor of Onivyde (liposomal irinotecan). Jonathan B. Fitzgerald is an employee of Merrimack. Charles Noble is a stockholder in Merrimack.
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