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

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.MethodsPatients 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.ResultsA 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 Cmax, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher Cmax 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.ConclusionsPEP02 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.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…We observed a strong and significant correlation between average irinotecan levels in lesions and the time on treatment for each patient. Furthermore, the concentrations of irinotecan measured in biopsies at 72 hours after administration of nal-IRI were far higher than could be accounted for by microcirculatory levels for total irinotecan and its liposomal encapsulation (15,50), consistent with intratumoral deposition of nal-IRI. The composition of nal-IRI precluded any direct IHC-based analysis of the liposomal distribution in post-treatment FFPE samples from our patients.…”

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

“…Detailed eligibilities, methods, and clinical results of these studies have been described previously 3, 7, 8, 10, 11, 12. For example, the eligibility criteria in Study NAPOLI‐1 included adequate bone marrow reserve (absolute neutrophil count (ANC) >1,500 cells/μL, platelet >10 6 cells/μL, hemoglobin >9 g/dL), adequate renal function (serum creatinine (SCr) ≤1.5 upper limit of normal (ULN)), and adequate liver function (bilirubin ≤ULN, albumin ≥3.0 g/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of ≤2.5 ULN or ≤5 ULN if liver metastases were present).…”

“…PK sample collection during the first cycle consisted of intense sampling in early studies7, 8, 10, 11, 12 and sparse sampling in the phase III study NAPOLI‐1 ( Table S1 ) 3. The analytes measured include tIRI (encapsulated plus unencapsulated irinotecan) and tSN38.…”

“…The analytes measured include tIRI (encapsulated plus unencapsulated irinotecan) and tSN38. In the first study, the levels of encapsulated irinotecan were found to be indistinguishable from tIRI10; therefore, only tIRI were measured in the subsequent studies. Samples collected after second dose administrations were excluded because of suspected inaccuracy in the sampling times.…”

Nanomedicine developments in the treatment of metastatic pancreatic cancer: focus on nanoliposomal irinotecan

“…The first-in-human clinical trial of nal-IRI, conducted in Taiwan by Chang et al, 38 consisted of a Phase I dose-escalation study in patients with advanced refractory solid tumors, including cervical, breast, neuroendocrine, pancreatic, non-smallcell lung, and thymic cancers. In total, eleven patients were enrolled across three dose levels, with the maximal tolerated dose (MTD) established at 120 mg/m 2 on an every-3-week schedule.…”