title: Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck.
abstract: OBJECTIVE
  This study (EGF100262) sought to establish the recommended phase II dose of lapatinib with chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
  
  
  METHODS
  Patients were enrolled onto cohorts of escalating lapatinib dose (500, 1,000, and 1,500 mg/d). Patients received 1 week of lapatinib alone followed by 6.5 to 7 weeks of the same dose of lapatinib plus radiotherapy 66 to 70 Gy and cisplatin 100 mg/m(2) on days 1, 22, and 43 of radiotherapy. End points included safety/tolerability and clinical activity.
  
  
  RESULTS
  Thirty-one patients were enrolled (seven patients in each of the 500- and 1,000-mg cohorts and three in the 1,500-mg cohort; an additional 14 patients were enrolled at 1,500 mg in a safety cohort). Dose-limiting toxicities (DLTs) included perforated ulcer in one patient in the 500-mg cohort and transient elevation of liver enzymes in one patient in the 1,000-mg cohort. No DLTs were observed in the 1,500-mg cohort. Therefore, the recommended phase II dose was defined as lapatinib 1,500 mg/d with chemoradiotherapy. The most common grade 3 to 4 adverse events were radiation mucositis, radiation dermatitis, lymphopenia, and neutropenia. No patients experienced drug-related symptomatic cardiotoxicity, and no interstitial pneumonitis was reported. The overall response rate was 81% (65% at the recommended phase II dose).
  
  
  CONCLUSIONS
  The recommended phase II dose is lapatinib 1,500 mg/d with chemoradiotherapy in patients with LA SCCHN; this regimen is associated with an acceptable tolerability profile. Given these findings, randomized phase II and III studies of lapatinib plus chemoradiotherapy have been initiated.
authors.affiliation: Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, 203 Fulham Rd, London SW3 6JJ, United Kingdom. Kevin.Harrington@icr.ac.uk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Iman A
authors.initials: IA
authors.lastname: El-Hariry
authors.forename: Clare S
authors.initials: CS
authors.lastname: Holford
authors.forename: Antoine
authors.initials: A
authors.lastname: Lusinchi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.forename: Dominique
authors.initials: D
authors.lastname: Rosine
authors.forename: Mary
authors.initials: M
authors.lastname: Tanay
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
authors.forename: Jennifer
authors.initials: J
authors.lastname: Matthews
authors.forename: Consuelo
authors.initials: C
authors.lastname: D'Ambrosio
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Jagannatha S
authors.initials: JS
authors.lastname: Pandeshwara
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib