title: A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer.
abstract: OBJECTIVE
  The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies.
  
  
  METHODS
  Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses.
  
  
  RESULTS
  Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (>25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (C(max) and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response.
  
  
  CONCLUSIONS
  Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA. quincchu@cancerboard.ab.ca
authors.forename: Quincy S C
authors.initials: QS
authors.lastname: Chu
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cianfrocca
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Goldstein
authors.forename: Meg
authors.initials: M
authors.lastname: Gale
authors.forename: Nicholas
authors.initials: N
authors.lastname: Murray
authors.forename: Jill
authors.initials: J
authors.lastname: Loftiss
authors.forename: Nikita
authors.initials: N
authors.lastname: Arya
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: Lini
authors.initials: L
authors.lastname: Pandite
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Fleming
authors.forename: Elaine
authors.initials: E
authors.lastname: Paul
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D000077341:Lapatinib; D000077289:Letrozole; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D009570:Nitriles; D011799:Quinazolines; D014230:Triazoles; D000077341:Lapatinib; D000077289:Letrozole