title: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.
abstract: OBJECTIVE
  This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors.
  
  
  METHODS
  Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks.
  
  
  RESULTS
  Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose.
  
  
  CONCLUSIONS
  Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.
authors.affiliation: The Sarah Cannon Research Institute, 250 25th Avenue N, Suite 110, Nashville, TN 37203, USA. hburris@tnonc.com
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
authors.forename: Bert
authors.initials: B
authors.lastname: O'Neil
authors.forename: Paul K
authors.initials: PK
authors.lastname: Marcom
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Beth
authors.initials: B
authors.lastname: Overmoyer
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Smith
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: Andrew
authors.initials: A
authors.lastname: Stead
authors.forename: Steve
authors.initials: S
authors.lastname: Mangum
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012449:Safety; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases