title: A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors.
abstract: OBJECTIVE
  We conducted a phase I study to determine the recommended dose of selenomethionine (SLM) in combination with irinotecan that consistently results in a protective plasma selenium (Se) concentrations > 15 microM after 1 week of SLM loading.
  
  
  METHODS
  A 3-3 standard escalation design was followed. SLM was given orally twice daily (BID) for one week (loading) followed by continuous once daily (QD) dosing (maintenance). Seven dose levels of selenomethionine were investigated. Irinotecan was given intravenously at a fixed standard weekly dose, starting on the first day of maintenance SLM.
  
  
  RESULTS
  Thirty-one patients were treated on study. Dose limiting diarrhea complicated by sepsis was noted in one of six patients at each of the dose-levels 1 and 7. Dose-levels > or = 5 (4,800 mcg/dose loading maintenance) resulted in day 8 Se concentrations >15 microM while dose-level 7 (7,200 mcg/dose loading and maintenance) resulted in day 8 Se concentrations > 20 muM. No significant variations in SN-38 or biliary index were noted between weeks 1 and 4 of treatment. Despite achieving target Se concentrations, gastrointestinal and bone marrow toxicities were common and irinotecan dose modification was prevalent. Objective responses were seen in two patients and nine patients had disease control for 6 months or longer.
  
  
  CONCLUSIONS
  Selenomethionine can be escalated safely to 7,200 mcg BID x 1 week followed by 7,200 mcg QD in combination with a standard dose of irinotecan. No major protection against irinotecan toxicity was established; however, interesting clinical benefits were noted-supporting the investigation of this combination in future efficacy trials.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. marwan.fakih@roswellpark.org
authors.forename: Marwan G
authors.initials: MG
authors.lastname: Fakih
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pendyala
authors.forename: William
authors.initials: W
authors.lastname: Brady
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Mary E
authors.initials: ME
authors.lastname: Ross
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: Vladimir
authors.initials: V
authors.lastname: Badmaev
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Prey
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012645:Selenomethionine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000077146:Irinotecan; D012645:Selenomethionine; D002166:Camptothecin