title: A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors.
abstract: PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors.
  
  
  
  Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m2(dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m2and LV 200 mg/m2on days 1 and 8, every 3 weeks.
  
  
  
  A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m2(two patients). DLT was observed in four patients, two at the 100 mg/m2dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m2dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m2. The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level.
  
  
  
  The MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m2, which will be the recommended dose for future studies.
  
  
  
  The trial was retrospectively registered ( NCT02884128 ) with date of registration: August 12, 2016.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan, 704, Taiwan.|Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Nai-Jung
authors.initials: NJ
authors.lastname: Chiang
authors.affiliation: Division of Hematology and Oncology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Tsu-Yi
authors.initials: TY
authors.lastname: Chao
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Ruey-Kuen
authors.initials: RK
authors.lastname: Hsieh
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Cheng-Hsu
authors.initials: CH
authors.lastname: Wang
authors.affiliation: PharmaEngine, Inc, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Wang
authors.affiliation: PharmaEngine, Inc, Taipei, Taiwan.
authors.forename: C Grace
authors.initials: CG
authors.lastname: Yeh
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan, 704, Taiwan. leochen@nhri.og.tw.|Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. leochen@nhri.og.tw.|Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. leochen@nhri.og.tw.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004338:Drug Combinations; D016903:Drug Monitoring; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000071184:Pharmacogenomic Variants; D013395:Sucrose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D008081:Liposomes; D013395:Sucrose; C584112:irinotecan sucrosofate; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: 5-fluorouracil; Dose-limiting toxicity; Liposomal irinotecan; Maximum tolerated dose