Jennifer L Clarke1,2, Annette M Molinaro3, Juan R Cabrera3, Ashley A DeSilva3, Jane E Rabbitt3, Joshua Prey4, Daryl C Drummond5, Jaeyeon Kim5, Charles Noble5, Jonathan B Fitzgerald5, Susan M Chang3, Nicholas A Butowski3, Jennie W Taylor3,6, John W Park7, Michael D Prados3. 1. 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. 2. Department of Neurology, University of California, San Francisco, 400 Parnassus Avenue, San Francisco, CA, 94122, USA. clarkej@neurosurg.ucsf.edu. 3. Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA. 4. Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. 5. Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA. 6. Department of Neurology, University of California, San Francisco, 400 Parnassus Avenue, San Francisco, CA, 94122, USA. 7. Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St., San Francisco, CA, 94115, USA.
Abstract
PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Nal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.
PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Nal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.
Authors: Margarita Gutova; Linda Flores; Vikram Adhikarla; Lusine Tsaturyan; Revathiswari Tirughana; Soraya Aramburo; Marianne Metz; Joanna Gonzaga; Alexander Annala; Timothy W Synold; Jana Portnow; Russell C Rockne; Karen S Aboody Journal: Front Oncol Date: 2019-02-19 Impact factor: 6.244