PGx320 Tykerb TEACH EGF105485 liver safety pharmacogenetics

Trial description: Lapatinib is a small molecule ErbB1/ErbB2 tyrosine kinase inhibitor (TKI), for the treatment of a variety of cancers, including breast cancer. Lapatinib was approved by the Food and Drug Administration (FDA) in the US on March 13, 2007 in combination with capecitabine (Xeloda) for the treatment of patients with advanced or metastatic breast cancer (MBC) whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab (Herceptin). In January 2010, lapatinib was approved in combination with letrozole for treatment of postmenopausal women with hormone positive metastatic breast cancer that overexpress HER2 receptor for whom hormonal therapy is indicated. With consideration of the FDA guidance document on distinguishing signals of drug induced liver injury (DILI), GSK has been conducting retrospective pharmacogenetic analyses of the laboratory and clinical data from studies of lapatinib monotherapy and lapatinib in combination with other anti-cancer agents in patients with various stages of breast cancer. Previous retrospective pharmacogenetic studies using data from thirteen advanced/metastatic breast cancer trials have identified and confirmed four genetic variants in the class II major histocompatibility complex (MHC) locus that are associated with lapatinib-induced alanine aminotransferase (ALT) elevation. This study prospectively defines an analysis strategy for the reporting of the pharmacogenetic (PGx) data from EGF105485 (TEACH). The TEACH study (Tykerb Evaluation After Chemotherapy) is a large, randomized, placebo controlled study of lapatinib treated patients with early stage, erbB2 over expressing breast cancer. All available lapatinib-treated consented DNA samples from EGF105485 will be included in the PGx analysis. The PGx analysis population will consist of the subjects enrolled in the clinical study EGF105485 who provided written informed consent for PGx research, provided an adequate blood sample for genotyping and were successfully genotyped for at least one of the four genetic variants under study, and have valid clinical data available.The primary analysis will: 1) determine estimates of the four previously confirmed MHC genetic variants (HLA-DQA1*02:01, HLA-DRB1*07:01, HLA-DQB1*02:02, and one single nucleotide polymorphism in TNXB(rs12153855)) for associations with elevated isolated ALT and concurrent ALT/total bilirubin (TBL) in this patient population, and 2) determine the predictive value of these genetic markers in clinical management of liver safety in lapatinib treated patients. The present analysis will use the same case-control definitions as used in previous retrospective studies, to maximize comparability. These strict case-control definitions constrain baseline values to be within the normal ranges (≤1 x ULN) and requires a minimum treatment duration of thirteen weeks in controls. There are some patients that will be neither strict cases nor controls by this definition, so in addition, broader definitions of cases and controls will be used in order to evaluate measures of clinical utility amongst the entire available sample of lapatinib-treated patients. Additional exploratory analyses may be conducted to further our knowledge about the association of these pre-specified genetic variants with hepatobiliary adverse events.