title: A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma.
abstract: 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/m2intravenously every 3 weeks with dose increases in 60 mg/m2increments. HT patients were started at 60 mg/m2, with dose increases in 30 mg/m2increments. 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.
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA. clarkej@neurosurg.ucsf.edu.|Department of Neurology, University of California, San Francisco, 400 Parnassus Avenue, San Francisco, CA, 94122, USA. clarkej@neurosurg.ucsf.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Clarke
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cabrera
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: DeSilva
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Rabbitt
authors.affiliation: Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Prey
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.
authors.forename: Daryl C
authors.initials: DC
authors.lastname: Drummond
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.
authors.forename: Jaeyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Noble
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Fitzgerald
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Butowski
authors.affiliation: 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.
authors.forename: Jennie W
authors.initials: JW
authors.lastname: Taylor
authors.affiliation: Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St., San Francisco, CA, 94115, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D005910:Glioma / Q000188:drug therapy*; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008081:Liposomes; D000099148:UGT1A1 Enzyme
keywords: Chemotherapy; Glioblastoma; High-grade glioma; Irinotecan; Liposomes