title: Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies.
abstract: OBJECTIVE
  This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies.
  
  
  METHODS
  Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses.
  
  
  RESULTS
  Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m(2)/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and alpha-fluoro-beta-alanine, were not meaningfully altered by coadministration.
  
  
  CONCLUSIONS
  Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.
authors: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. quincchu@cancerboard.ab.ca
authors: Quincy S C
authors: QS
authors: Chu
authors: Garry
authors: G
authors: Schwartz
authors: Johann
authors: J
authors: de Bono
authors: Deborah A
authors: DA
authors: Smith
authors: Kevin M
authors: KM
authors: Koch
authors: Melissa J
authors: MJ
authors: Versola
authors: Lini
authors: L
authors: Pandite
authors: Nikita
authors: N
authors: Arya
authors: Jan
authors: J
authors: Curtright
authors: Ronald A
authors: RA
authors: Fleming
authors: Peter T C
authors: PT
authors: Ho
authors: Eric K
authors: EK
authors: Rowinsky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069287:Capecitabine; D002648:Child; D002675:Child, Preschool; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil