title: An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for human epidermal growth factor receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer.
abstract: BACKGROUND
  Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1-2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial.
  
  
  METHODS
  Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m(2)).
  
  
  RESULTS
  Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ≥ 7days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed.
  
  
  CONCLUSIONS
  Our recommended dose for phase II is lapatinib 1000mg/day and docetaxel 100mg/m(2) with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.
authors.affiliation: Institut Bergonié, INSERM U916, Bordeaux, France. h.bonnefoi@bordeaux.unicancer.fr
authors.forename: H
authors.initials: H
authors.lastname: Bonnefoi
authors.forename: K
authors.initials: K
authors.lastname: Zaman
authors.forename: M
authors.initials: M
authors.lastname: Debled
authors.forename: M
authors.initials: M
authors.lastname: Fiche
authors.forename: M
authors.initials: M
authors.lastname: Fournier
authors.forename: M
authors.initials: M
authors.lastname: Nobahar
authors.forename: J-Y
authors.initials: JY
authors.lastname: Pierga
authors.forename: K M
authors.initials: KM
authors.lastname: Koch
authors.forename: J
authors.initials: J
authors.lastname: Bartlett
authors.forename: A
authors.initials: A
authors.lastname: Zimmer
authors.forename: S
authors.initials: S
authors.lastname: Marreaud
authors.forename: J
authors.initials: J
authors.lastname: Bogaerts
authors.forename: D
authors.initials: D
authors.lastname: Cameron
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000077341:Lapatinib; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000077143:Docetaxel; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C508053:ERBB2 protein, human