Originally published as JCO Early Release 10.1200/JCO.2008.17.5349 on January 26 2009

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Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Kevin J. Harrington, Iman A. El-Hariry, Clare S. Holford, Antoine Lusinchi, Christopher M. Nutting, Dominique Rosine, Mary Tanay, Eric Deutsch, Jennifer Matthews, Consuelo D'Ambrosio, Simon J. Turner, Jagannatha S. Pandeshwara, Jean Bourhis

From the Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust; The Institute of Cancer Research, London; Oncology Medicine Development Center, GlaxoSmithKline R&D, Stockley Park, United Kingdom; Department of Radiation Oncology, Institut Gustave-Roussy, Paris, France; and Biomedical Data Science, GlaxoSmithKline Pharmaceuticals Ltd, Bangalore, India.

Corresponding author: Kevin J. Harrington, FRCP, Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, 203 Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: Kevin.Harrington{at}icr.ac.uk.

Purpose 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).

Patients and 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/m² 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).

Conclusion 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.

Both K.J.H. and I.A.E.-H. contributed equally to this work.

Supported by an unrestricted grant from GlaxoSmithKline (medical writing support also funded by GlaxoSmithKline).

Presented in part at the 42nd Annual Meeting of the American Society for Clinical Oncology, June 2-6, 2006, Atlanta, Georgia; at the 31st European Society for Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey; and at the Joint International Meeting of the European Head and Neck Society and European Society for Therapeutic Radiation and Oncology, February 22-24, 2007, Barcelona, Spain.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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