title: Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen, to explore its safety and pharmacokinetics, and to assess its antitumor activity in patients with advanced solid tumors.
  
  
  METHODS
  Forty-eight patients received the combination of raltitrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infusion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated every 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m(2) and from 85 to 130 mg/m(2) for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels.
  
  
  RESULTS
  Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2)). This combination was not myelosuppressive, eliciting only sporadic grades 3 and 4 neutropenia and/or thrombocytopenia without complications. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m(2) and oxaliplatin 130 mg/m(2)) was deemed to be the MTD. Eight confirmed partial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetics of both drugs did not suggest any drug interaction.
  
  
  CONCLUSIONS
  The combination of raltitrexed and oxaliplatin given as consecutive short infusions every 3 weeks seems to be an acceptable regimen that allows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2) every 3 weeks. Promising antitumor activity has been observed in patients with malignant mesothelioma.
authors.affiliation: Institut Gustave-Roussy, Villejuif, and AstraZeneca Pharmaceuticals, Cergy, France. fizazi@igr.fr
authors.forename: K
authors.initials: K
authors.lastname: Fizazi
authors.forename: M
authors.initials: M
authors.lastname: Ducreux
authors.forename: P
authors.initials: P
authors.lastname: Ruffié
authors.forename: M
authors.initials: M
authors.lastname: Bonnay
authors.forename: C
authors.initials: C
authors.lastname: Daniel
authors.forename: J C
authors.initials: JC
authors.lastname: Soria
authors.forename: C
authors.initials: C
authors.lastname: Hill
authors.forename: A
authors.initials: A
authors.lastname: Fandi
authors.forename: M
authors.initials: M
authors.lastname: Poterre
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: J P
authors.initials: JP
authors.lastname: Armand
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D011799:Quinazolines; D013876:Thiophenes; D000077150:Oxaliplatin; C068874:raltitrexed