Cancer chemotherapy and pharmacology

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

PMID 25577133


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. Patients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180xa0mg/m(2), was given as a 90-min intravenous infusion, every 3xa0weeks. A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180xa0mg/m(2) (four patients). DLT was observed in three patients, one at 120xa0mg/m(2) (grade 3 catheter-related infection) and two at 180xa0mg/m(2) (grade 4 neutropenia lasting for >3xa0days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other). MTD was determined as 120xa0mg/m(2). 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 180xa0mg/m(2). Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1*6/*28. Two patients had objective tumor response. PEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120xa0mg/m(2), which will be the recommended dose for future studies.

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Irinotecan hydrochloride, topoisomerase inhibitor
C33H38N4O6 · HCl