title: Evaluation of lapatinib and topotecan combination therapy: tissue culture, murine xenograft, and phase I clinical trial data.
abstract: OBJECTIVE
  Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial.
  
  
  METHODS
  The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial.
  
  
  RESULTS
  Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m2 topotecan i.v. on days 1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization.
  
  
  CONCLUSIONS
  The lapatinib/topotecan combination is well tolerated and warrants further study.
authors.affiliation: Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. molina.julian@mayo.edu
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Rubin
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez-Peralta
authors.forename: Robert
authors.initials: R
authors.lastname: Friedman
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: Tona M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Jewell
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Felten
authors.forename: Sumithra
authors.initials: S
authors.lastname: Mandrekar
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D019772:Topotecan