title: A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients.
  
  
  METHODS
  Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m2/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000.
  
  
  RESULTS
  Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug-drug interactions.
  
  
  CONCLUSIONS
  Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m2/day.
authors.affiliation: Hôpital Cochin, Université Paris 5, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
authors.forename: Carmen
authors.initials: C
authors.lastname: Kahatt
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bertheault-Cvitkovic
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Stephen
authors.initials: S
authors.lastname: Shibata
authors.forename: Werner
authors.initials: W
authors.lastname: Hilgers
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Garry
authors.initials: G
authors.lastname: Weems
authors.forename: Ajit
authors.initials: A
authors.lastname: Shah
authors.forename: John R
authors.initials: JR
authors.lastname: MacDonald
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; D003841:Deoxycytidine; D000069287:Capecitabine; C102714:irofulven; D005472:Fluorouracil