title: Combination vinorelbine and capecitabine for metastatic breast cancer using a non-body surface area dosing scheme.
abstract: OBJECTIVE
  This study sought to determine the maximum tolerated dose of flat-dosed vinorelbine in combination with capecitabine in patients with metastatic breast cancer. At the time of study initiation, it was anticipated that vinorelbine would be developed as an oral capsule. A flat dosing scheme of both drugs was used to facilitate development of the oral regimen, and because neither drug's clearance is associated with body surface area (BSA), pharmacokinetic and pharmacogenetic endpoints were explored.
  
  
  METHODS
  Capecitabine was administered orally at 3,000 mg/day on days 1-14. The starting dose of vinorelbine was 20 mg intravenously on days 1 and 8 of a 21-day cycle. The vinorelbine dose was escalated until dose limiting toxicity (DLT). Vinorelbine pharmacokinetics were measured after the first dose. Patients underwent genotype analysis for polymorphisms in the CYP3A5 gene, and the erythromycin breath test (ERMBT), a phenotypic test of CYP3A enzyme activity.
  
  
  RESULTS
  Twenty five eligible patients were enrolled. Hematologic DLT was seen at the 50 and 45 mg vinorelbine doses; thus the recommended dose is 40 mg on days 1 and 8. Response rate was 30%, and disease stabilization rate was 64% (all dose levels included). Vinorelbine clearance was not associated with ERMBT, BSA, or age. CYP3A5 genotype in this small sample did not have an obvious relationship to clearance or toxicity.
  
  
  CONCLUSIONS
  A non-BSA based dosing scheme of capecitabine and vinorelbine is safe and efficacious. BSA did not affect vinorelbine clearance. We recommend future studies with capecitabine and/or vinorelbine to compare the safety and efficacy of flat dosed versus BSA-dosed treatment.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA. aschott@umich.edu
authors.forename: Anne F
authors.initials: AF
authors.lastname: Schott
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Vered
authors.initials: V
authors.lastname: Sterns
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Baker
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001830:Body Surface Area; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001944:Breath Tests; D000069287:Capecitabine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004917:Erythromycin / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D005838:Genotype; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000077235:Vinorelbine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003841:Deoxycytidine; D014747:Vinblastine; D004917:Erythromycin; D000069287:Capecitabine; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000077235:Vinorelbine; D005472:Fluorouracil