title: Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2.
abstract: BACKGROUND
  To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab.
  
  
  METHODS
  In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated.
  
  
  RESULTS
  Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1.
  
  
  CONCLUSIONS
  The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.
authors.affiliation: Department of Medical Oncology, Institut Curie - Hôpital René Huguenin 35 rue Daily, 92210 Saint-Cloud, France. etienne.brain@curie.net
authors.forename: E
authors.initials: E
authors.lastname: Brain
authors.forename: N
authors.initials: N
authors.lastname: Isambert
authors.forename: F
authors.initials: F
authors.lastname: Dalenc
authors.forename: V
authors.initials: V
authors.lastname: Diéras
authors.forename: J
authors.initials: J
authors.lastname: Bonneterre
authors.forename: K
authors.initials: K
authors.lastname: Rezai
authors.forename: M
authors.initials: M
authors.lastname: Jimenez
authors.forename: F
authors.initials: F
authors.lastname: Mefti-Lacheraf
authors.forename: E
authors.initials: E
authors.lastname: Cottura
authors.forename: P
authors.initials: P
authors.lastname: Tresca
authors.forename: L
authors.initials: L
authors.lastname: Vanlemmens
authors.forename: C
authors.initials: C
authors.lastname: Mahier-Aït Oukhatar
authors.forename: F
authors.initials: F
authors.lastname: Lokiec
authors.forename: P
authors.initials: P
authors.lastname: Fumoleau
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077235:Vinorelbine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine