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Clinical Trial
. 2015 Mar;75(3):579-86.
doi: 10.1007/s00280-014-2671-x. Epub 2015 Jan 11.

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

T C Chang  1 , H S Shiah, C H Yang, K H Yeh, A L Cheng, B N Shen, Y W Wang, C G Yeh, N J Chiang, J Y Chang, L T Chen
Affiliations
Clinical Trial

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

T C Chang et al. Cancer Chemother Pharmacol. 2015 Mar.

Abstract

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/m(2), 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/m(2) (four patients). DLT was observed in three patients, one at 120 mg/m(2) (grade 3 catheter-related infection) and two at 180 mg/m(2) (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/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 180 mg/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.

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/m(2), which will be the recommended dose for future studies.

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Figures

Fig. 1
Fig. 1
Plasma concentration–time profiles of a encapsulated CPT-11 (PEP02) and b SN-38 at 60, 120 and 180 mg/m2 dose level of PEP02
Fig. 2
Fig. 2
Plasma concentration–time profiles of encapsulated CPT-11 (PEP02) and total CPT-11 at 120 mg/m2 dose level of PEP02
Fig. 3
Fig. 3
Plasma concentration–time profiles of a total CPT-11 and b SN-38 in subjects at 180 mg/m2 dose level of PEP02
See this image and copyright information in PMC

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