A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma
- 309 Downloads
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.
- 1.Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C et al (2015) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neurooncology 17(Suppl 4):iv1–iv62Google Scholar
- 4.Kang MH, Wang J, Makena MR, Lee JS, Paz N, Hall CP et al (2015) Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing’s family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression. Clin Cancer Res Off J Am Assoc Cancer Res 21(5):1139–1150CrossRefGoogle Scholar
- 6.Chen PY, Ozawa T, Drummond DC, Kalra A, Fitzgerald JB, Kirpotin DB et al (2013) Comparing routes of delivery for nanoliposomal irinotecan shows superior anti-tumor activity of local administration in treating intracranial glioblastoma xenografts. Neurooncology 15(2):189–197Google Scholar
- 8.Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT et al (2013) A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol Off J Eur Soc Med Oncol ESMO 24(6):1567–1573CrossRefGoogle Scholar
- 9.Ramanathan RK, Korn RL, Sachdev JC, Fetterly GJ, Jameson G, Marceau K et al (2014) Lesion characterization with ferumoxytol MRI in patients with advanced solid tumors and correlation with treatment response to MM-398, nanoliposomal irinotecan (nal-IRI). Eur J Cancer 50(Suppl 6):87 (abstract 261)CrossRefGoogle Scholar
- 10.Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G et al (2016) Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet (London, England) 387(10018):545–557CrossRefGoogle Scholar
- 17.Krauze MT, Noble CO, Kawaguchi T, Drummond D, Kirpotin DB, Yamashita Y et al (2007) Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts. Neurooncology 9(4):393–403Google Scholar