title: Phase I and pharmacokinetic study of IHL-305 (PEGylated liposomal irinotecan) in patients with advanced solid tumors.
abstract: OBJECTIVE
  IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D).
  
  
  METHODS
  In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group.
  
  
  RESULTS
  Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m(2) every 28 days and 80 mg/m(2) every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months.
  
  
  CONCLUSIONS
  IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.
authors.affiliation: Sarah Cannon Research Institute, 250 25th Avenue, Nashville, TN 37203, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Keedy
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008081:Liposomes; D011092:Polyethylene Glycols; D000099148:UGT1A1 Enzyme