title: Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gynecology, Linkuo Chang-Gung Memorial Hospital, No.5, Fu-Hsing Street, Kuei-shan Hsiang, Taoyuan, 33305, Taiwan.
authors.forename: T C
authors.initials: TC
authors.lastname: Chang
authors.forename: H S
authors.initials: HS
authors.lastname: Shiah
authors.forename: C H
authors.initials: CH
authors.lastname: Yang
authors.forename: K H
authors.initials: KH
authors.lastname: Yeh
authors.forename: A L
authors.initials: AL
authors.lastname: Cheng
authors.forename: B N
authors.initials: BN
authors.lastname: Shen
authors.forename: Y W
authors.initials: YW
authors.lastname: Wang
authors.forename: C G
authors.initials: CG
authors.lastname: Yeh
authors.forename: N J
authors.initials: NJ
authors.lastname: Chiang
authors.forename: J Y
authors.initials: JY
authors.lastname: Chang
authors.forename: L T
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010597:Pharmacogenetics; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008081:Liposomes; D000099148:UGT1A1 Enzyme