Background: Treatment options for recurrent malignant glioma are limited. 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, liposomal irinotecan (nal-IRI, also MM-398, PEP02) demonstrates prolongation of drug exposure and higher tissue levels of drug due to slower metabolism. A Phase I study was undertaken in advanced solid tumor patients in Taiwan, and the MTD was 120 mg/m²; UGT1A1 genotyping was not prospectively undertaken in that solid tumor study. Objectives: To assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent malignant glioma stratified based on UGT1A1 genotyping. Methods: This Phase I study in recurrent malignant glioma stratified patients by UGT1A1 status, to homozygous WT (“WT”) vs heterozygous WT/*28 (“HT”). Patients who were homozygous *28 were ineligible. Eligibility criteria included age > = 18, KPS > = 60, not on enzyme-inducing drugs (including enzyme-inducing seizure medications), and no prior treatment with irinotecan. The design was a standard 3+3 Phase I design. Patients who were WT were started at 120 mg/m² (the MTD from the Taiwanese study) with dose increases in 60 mg/m² increments. Patients who were HT were started at 60 mg/m², with dose increases in 30 mg/m²increments. Dosing was given IV every 3 weeks. The DLT assessment period was 1 cycle (21 days). Results: In the WT cohort, the MTD was 120 mg/m². In the HT cohort, the MTD was 150 mg/m². DLTs in both cohorts included diarrhea, some with associated dehydration and/or fatigue. Analysis of PK data is in process, and will be presented at the meeting. Conclusions: Nal-IRI had no unexpected toxicities when given via IV. The toxicity profile of the drug was felt acceptable to move forward with additional testing using convection-enhanced delivery into intracranial tumors, and such a Phase I study is currently enrolling at our institution. Clinical trial information: NCT00734682