title: A phase I study of UGT1A1 *28/*6 genotype-directed dosing of irinotecan (CPT-11) in Korean patients with metastatic colorectal cancer receiving FOLFIRI.
abstract: OBJECTIVE
  A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patients with metastatic colorectal cancer receiving first-line FOLFIRI chemotherapy.
  
  
  METHODS
  Patients were genotyped for UGT1A1 and stratified according to the number of defective alleles (DA; *28 and *6). The irinotecan dose was escalated with a fixed dose of 5-fluorouracil and leucovorin in a standard 3 + 3 design.
  
  
  RESULTS
  In 43 enrolled patients, the maximum tolerated dose (MTD) was 300 mg/m² for the 1 DA group, while the MTD was not reached for the 0 DA group with 1 dose-limiting toxicity (DLT) at 330 mg/m² and for the 2 DA group with 0 DLT at 150 mg/m². Because of the risk of being exposed to unsafe doses, the trial was terminated before the MTD was reached in the 0 DA and 2 DA groups. The recommended doses were 300 (0 DA), 270 (1 DA) and 150 (0 DA) mg/m². The 2 DA group displayed 27% lower SN-38 exposure levels relative to the 0 and 1 DA groups (95% CI, 0.47-1.15).
  
  
  CONCLUSIONS
  The MTD of irinotecan differed according to the UGT1A1 genotype, and higher doses of irinotecan are feasible with sLV5FU2 compared to the present regulatory approved doses.
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.forename: Kyun Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Ho-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D056910:Republic of Korea; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme