title: Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer.
abstract: OBJECTIVE
  The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer.
  
  
  METHODS
  Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination.
  
  
  RESULTS
  A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone.
  
  
  CONCLUSIONS
  The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Dr, Room 473, Indianapolis, IN 46202, USA. astornio@iupui.edu
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Storniolo
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
authors.forename: Beth
authors.initials: B
authors.lastname: Overmoyer
authors.forename: Paula
authors.initials: P
authors.lastname: Silverman
authors.forename: Nancy W
authors.initials: NW
authors.lastname: Peacock
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
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: Elaine
authors.initials: E
authors.lastname: Paul
authors.forename: Lini
authors.initials: L
authors.lastname: Pandite
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Fleming
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lebowitz
authors.forename: Peter T C
authors.initials: PT
authors.lastname: Ho
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018570:Risk Assessment; D016019:Survival Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab