Cancer Therapy: Clinical A Phase I and Pharmacokinetic Study of Oral Lapatinib Administered Once or Twice Daily in Patients with Solid Malignancies

Purpose: This study determined the range of tolerable doses, clinical safety, pharmacokinetics, and preliminary evidence of clinical activity following once or twice daily administration of lapatinib in patients with solid malignancies. Experimental Design: Cancer patients (n = 81) received oral doses of lapatinib ranging from 175 to 1,800 mg once daily or 500 to 900 mg twice daily. Clinical assessments of safety and antitumor activity were recorded and blood was sampled for pharmacokinetic assessments. The effect of a low-fat meal on lapatinib pharmacokinetics was assessed in a subset of patients. Results: Lapatinib was well tolerated, such that dose escalation was limited at 1,800 mg once daily only by pill burden. Twice-daily dosing was implemented to further explore tolerability, and was limited by diarrhea to 500 mg twice daily. The most commonly reported adverse events with once-daily dosing were diarrhea (48%), nausea (40%), rash (40%), and fatigue (38%) and with twice-daily dosing were diarrhea (85%), rash (54%), and nausea (34%). Lapatinib serum concentrations accumulated upon repeated dosing, increasing nearly in proportion with dose, and were significantly increased when dosed with food or administered twice daily. One patient with head and neck cancer achieved a confirmed complete response and 22 patients had stable disease of ≥8 weeks including three patients with stable disease of >10 months (renal, lung, and salivary gland cancers). Conclusion: Lapatinib was well tolerated following once and twice daily administration. Systemic exposure to lapatinib was dependent on the dose, duration and frequency of dosing, and prandial state. Clinical activity was observed. (Clin Cancer Res 2009;15 (21):6702–8) The aberrant activation of growth factor receptors plays an important role in human cancers (1). Overexpression of epidermal growth factor receptor (ErbB1) and HER2 (ErbB2) occurs in many epithelial tumors, and clinical studies suggest that both receptors may be implicated in tumor etiology and progression (1, 2). Overexpression of erbB1 and erbB2 receptors has been reported in head and neck carcinomas (3, 4), breast cancer (5), and non–small cell lung cancer (6) and has been associated with poor prognosis and reduced survival in patients with cancer (6–8). Clinical studies have shown activity of inhibitors of erbB1 or erbB2 receptor function in patients with advanced malignancies (9–14). ErbB receptor tyrosine kinase activation requires receptor dimerization and erbB2 is the preferred dimerization partner for all other members of the erbB family. Heterodimerization of erbB receptors leads to a more aggressive tumorigenic phenotype (15, 16). Inhibition of both erbB1 and erbB2 receptors could have significant therapeutic advantages over current therapies that target either erbB1 or erbB2. Lapatinib (Tykerb/Tyverb; GlaxoSmithKline), a member of the 4-anilinoquinazoline class of kinase inhibitors, is a reversible inhibitor of erbB1 and erbB2 tyrosine kinases. Lapatinib abrogates phosphorylation and activation of receptor-mediated downstream signal transduction in erbB1and erbB2-expressing tumor cell lines and xenografts (17, 18). Initial phase I studies conducted in healthy volunteers showed that lapatinib was well tolerated at the doses studied (10to 250-mg single doses and 25to 175-mg repeat doses; ref. 19). Authors' Affiliations: The Sarah Cannon Cancer Center, Nashville, Tennessee; Arizona Cancer Center, Tucson, Arizona; GlaxoSmithKline, Research Triangle Park, North Carolina; and University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin Received 2/12/09; revised 7/23/09; accepted 7/25/09; published OnlineFirst 10/13/09. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Howard A. Burris III, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203. Phone: 615329-7276; Fax: 615-340-1576; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0369 6702 Clin Cancer Res 2009;15(21) November 1, 2009 www.aacrjournals.org Research. on July 12, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst October 13, 2009; DOI: 10.1158/1078-0432.CCR-09-0369