title: Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics.
abstract: OBJECTIVE
  Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen.
  
  
  METHODS
  Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 mg/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined.
  
  
  RESULTS
  Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one study and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2). At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients.
  
  
  CONCLUSIONS
  This combination is feasible, with activity in 5-FU-resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.
authors.affiliation: Hôpital Paul Brousse, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Wasserman
authors.forename: C
authors.initials: C
authors.lastname: Cuvier
authors.forename: F
authors.initials: F
authors.lastname: Lokiec
authors.forename: F
authors.initials: F
authors.lastname: Goldwasser
authors.forename: S
authors.initials: S
authors.lastname: Kalla
authors.forename: D
authors.initials: D
authors.lastname: Méry-Mignard
authors.forename: M
authors.initials: M
authors.lastname: Ouldkaci
authors.forename: A
authors.initials: A
authors.lastname: Besmaine
authors.forename: G
authors.initials: G
authors.lastname: Dupont-André
authors.forename: M
authors.initials: M
authors.lastname: Mahjoubi
authors.forename: M
authors.initials: M
authors.lastname: Marty
authors.forename: J L
authors.initials: JL
authors.lastname: Misset
authors.forename: E
authors.initials: E
authors.lastname: Cvitkovic
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D002277:Carcinoma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D004067:Digestive System Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D005260:Female; D005878:Gilbert Disease / Q000150:complications; D005965:Glucuronates; D020719:Glucuronides / Q000097:blood; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D010984:Platinum / Q000097:blood; D016896:Treatment Outcome
chemical_list: C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D005965:Glucuronates; D020719:Glucuronides; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D000077146:Irinotecan; D002166:Camptothecin