title: Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics.
abstract: OBJECTIVE
  The present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNalpha2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated.
  
  
  METHODS
  A total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m2 twice daily orally, days 1-14, 22-36) and rHuIFNalpha2a (1.5 or 3.0 MU/m2 s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chroatography/mass spectrometry in ten patients.
  
  
  RESULTS
  The toxicity of combined capecitabine and rHuIFNalpha2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m2 twice daily and rHuIFNalpha2a 3.0 MU/m2 three times weekly. One patient had a partial response of a liver lesion (duration > 200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5'-deoxy-5-fluorouridine, 5-fluorouracil and alpha-fluoro-beta-alanine) were similar to those reported by other authors. There was rapid conversion to 5'-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h.
  
  
  CONCLUSIONS
  The combination of capecitabine and rHuIFNalpha2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNalpha2a 3.0 MU/m2 s.c. three times weekly and oral capecitabine 1000 mg/m2 twice daily for 2 weeks. No evidence of an effect of rHuIFNalpha2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.
authors.affiliation: Experimental Therapeutics Program, Cleveland Clinic Taussig Cancer Center, OH 44195, USA.
authors.forename: D Z
authors.initials: DZ
authors.lastname: Chang
authors.forename: T
authors.initials: T
authors.lastname: Olencki
authors.forename: G T
authors.initials: GT
authors.lastname: Budd
authors.forename: D
authors.initials: D
authors.lastname: Peereboom
authors.forename: R
authors.initials: R
authors.lastname: Ganapathi
authors.forename: B
authors.initials: B
authors.lastname: Osterwalder
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine; D002853:Chromatography, Liquid; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced
chemical_list: D016898:Interferon-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil