title: Optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first-line treatment of HER2-positive metastatic breast cancer.
abstract: BACKGROUND
  This phase IB, open-label, dose-escalation study evaluated the safety, tolerability, and optimally tolerated regimen (OTR) of lapatinib in combination with docetaxel and trastuzumab in patients with previously untreated stage IV metastatic breast cancer (MBC) tumors overexpressing human epidermal growth factor receptor 2 (HER2).
  
  
  METHODS
  Evaluated dose regimens included lapatinib (500-1500 mg/day), docetaxel (triweekly; 60-100 mg/m&sup2;), and trastuzumab (weekly; 2 mg/kg fixed dose); prophylactic granulocyte colony-stimulating factor was included with regimens with ≥750 mg/day lapatinib. End points included OTR and safety/tolerability (primary), overall response rate (ORR), and pharmacokinetics (secondary).
  
  
  RESULTS
  None of the patients (N = 53) experienced dose-limiting toxic effects (DLTs) at the highest dose level; thus, the OTR of lapatinib with 100 mg/m(2) docetaxel was not determined. Common adverse events included diarrhea, nausea, alopecia, fatigue, and rash; grade 3/4 (≥2 patients) were neutropenia, diarrhea, leukopenia, peripheral neuropathy, and rash. Seven patients had DLTs (cycle 1). In 45 patients with measurable disease confirmed by bone scan, investigator-assessed ORR was 31%; without bone scan, confirmation was 64%; 8 patients without measurable disease were evaluated as stable. Lapatinib/docetaxel plasma concentrations were positively associated with complete response.
  
  
  CONCLUSIONS
  Lapatinib/docetaxel/trastuzumab is a feasible and well-tolerated treatment of untreated HER2-positive stage IV MBC. Two lapatinib/docetaxel OTR doses were recommended (1250 mg/75 mg/m&sup2;; 1000 mg/100 mg/m&sup2;).
  
  
  BACKGROUND
  NCT00251433.
authors.affiliation: All Ireland Cooperative Oncology Research Group, Dublin, Ireland. john.crown@icorg.ie
authors.forename: J
authors.initials: J
authors.lastname: Crown
authors.forename: M J
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: P
authors.initials: P
authors.lastname: Tresca
authors.forename: M
authors.initials: M
authors.lastname: Marty
authors.forename: M
authors.initials: M
authors.lastname: Espie
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: M
authors.initials: M
authors.lastname: DeSilvio
authors.forename: M R
authors.initials: MR
authors.lastname: Lau
authors.forename: D
authors.initials: D
authors.lastname: Kothari
authors.forename: K M
authors.initials: KM
authors.lastname: Koch
authors.forename: V
authors.initials: V
authors.lastname: Diéras
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D000077143:Docetaxel; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011092:Polyethylene Glycols; D011799:Quinazolines / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000627:therapeutic use; D043823:Taxoids / Q000097:blood / Q000627:therapeutic use; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077143:Docetaxel; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D000077341:Lapatinib; D011092:Polyethylene Glycols; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D043823:Taxoids; D000068878:Trastuzumab; C455861:pegfilgrastim; C508053:ERBB2 protein, human
keywords: HER2/ERBB2; docetaxel; lapatinib; metastatic breast cancer; trastuzumab; tyrosine kinase inhibitor