title: A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors.
abstract: OBJECTIVE
  This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol.
  
  
  METHODS
  Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design.
  
  
  RESULTS
  Seventy-six patients were entered onto 3 dosing schedules (58-245 mg/m(2)). The MTD was 115 mg/m(2) for the w × 3q4w schedule and 145 mg/m(2) for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer.
  
  
  CONCLUSIONS
  Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m(2) q14d or q21d.
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC)/TGen, Scottsdale, AZ, USA. gjameson@shc.org
authors.forename: Gayle S
authors.initials: GS
authors.lastname: Jameson
authors.forename: John T
authors.initials: JT
authors.lastname: Hamm
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Carlos
authors.initials: C
authors.lastname: Alemany
authors.forename: Stephen
authors.initials: S
authors.lastname: Anthony
authors.forename: Michele
authors.initials: M
authors.lastname: Basche
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: Allen
authors.initials: A
authors.lastname: Cohn
authors.forename: Ioana
authors.initials: I
authors.lastname: Hinshaw
authors.forename: Robert
authors.initials: R
authors.lastname: Jotte
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eldon
authors.forename: Robert
authors.initials: R
authors.lastname: Medve
authors.forename: Katrina
authors.initials: K
authors.lastname: Schroeder
authors.forename: Erica
authors.initials: E
authors.lastname: White
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D059004:Topoisomerase I Inhibitors; D011092:Polyethylene Glycols; C581703:etirinotecan pegol