Phase i study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients

Purpose: To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02, a novel liposome-encapsulated irinotecan, in patients with advanced refractory solid tumors. Methods: Patients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180 mg/m², was given as a 90-min intravenous infusion, every 3 weeks. Results: A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180 mg/m² (four patients). DLT was observed in three patients, one at 120 mg/m² (grade 3 catheter-related infection) and two at 180 mg/m² (grade 4 neutropenia lasting for >3 days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other). MTD was determined as 120 mg/m². Comparing with those after free-form irinotecan in the literature, the dose-normalized PK of SN-38 (the active metabolite) after PEP02 was characterized by lower C _max, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher C _max and AUC levels of SN-38 than those of the other three patients at 180 mg/m². Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1∗6/∗28. Two patients had objective tumor response. Conclusions: PEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120 mg/m², which will be the recommended dose for future studies.