title: A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study).
abstract: OBJECTIVE
  This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC).
  
  
  METHODS
  Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day.
  
  
  RESULTS
  Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months.
  
  
  CONCLUSIONS
  The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.
authors: Centre Georges-François Leclerc, Rue Professeur Marion, 21079 Dijon, France. Electronic address: pfumoleau@cgfl.fr.
authors: Pierre
authors: P
authors: Fumoleau
authors: GlaxoSmithKline, Research Triangle Park, 5 Moore Drive, 27709 Raleigh-Durham, United States. Electronic address: kevin.m.koch@gsk.com.
authors: Kevin M
authors: KM
authors: Koch
authors: Institut Curie, Centre René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France. Electronic address: etienne.brain@curie.net.
authors: Etienne
authors: E
authors: Brain
authors: Institut Curie, Centre René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France. Electronic address: francois.lokiec@curie.net.
authors: François
authors: F
authors: Lokiec
authors: Institut Curie, Centre René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France. Electronic address: keyvan.rezai@curie.net.
authors: Keyvan
authors: K
authors: Rezai
authors: Institut Jules Bordet, Boulevard de Waterloo 121, 1000 Brussels, Belgium. Electronic address: ahmad.awada@bordet.be.
authors: Ahmad
authors: A
authors: Awada
authors: Edinburgh Cancer Centre, Western General Hospital, Crewe Road South, EH4 2XR Edinburgh, United Kingdom. Electronic address: Larry.Hayward@nhslothian.scot.nhs.uk.
authors: Larry
authors: L
authors: Hayward
authors: European Organisation for Research and Treatment of Cancer, Avenue Mounier, 83/11, 1200 Brussels, Belgium. Electronic address: gwerutsky@gmail.com.
authors: Gustavo
authors: G
authors: Werutsky
authors: European Organisation for Research and Treatment of Cancer, Avenue Mounier, 83/11, 1200 Brussels, Belgium. Electronic address: jan.bogaerts@eortc.be.
authors: Jan
authors: J
authors: Bogaerts
authors: European Organisation for Research and Treatment of Cancer, Avenue Mounier, 83/11, 1200 Brussels, Belgium. Electronic address: sandrine.marreaud@eortc.be.
authors: Sandrine
authors: S
authors: Marréaud
authors: Institut Jules Bordet, Boulevard de Waterloo 121, 1000 Brussels, Belgium; Institut Jules Bordet (currently at Champalimaud Cancer Center), Av. de Brasília, s/n, 1400-038 Lisbon, Portugal. Electronic address: fatimacardoso@fundacaochampalimaud.pt.
authors: Fatima
authors: F
authors: Cardoso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011799:Quinazolines / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011799:Quinazolines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D000077341:Lapatinib
keywords: Breast cancer; Lapatinib; Pharmacokinetics; Phase 1 clinical trials; Tamoxifen