PGX7556: Pharmacogenetic Evaluation of FCGR in CLL patients treated with ofatumumab plus chloroambucil vs chloroambucil only

Trial description: GlaxoSmithKline (GSK) is developing ofatumumab (GSK1841157), an anti-CD20 monoclonal antibody (mAb), for the treatment of multiple oncology indications, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) and diffuse large B-cell lymphoma (DLBCL), as well as non-oncology indications including multiple sclerosis and rheumatoid arthritis. Ofatumumab was approved by the Food and Drug Administration (FDA) in 2009 for the treatment of CLL patients refractory to both alemtuzumab and fludarabine. Ofatumumab recognizes an epitope of the CD20 molecule distinct from the epitope of other CD20 mAbs, including the rituximab binding site, and induces cell lysis primarily through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). A significant body of research has been conducted and published regarding the association of Fc-gamma receptors (FCGR) 3A and 2A with the efficacy of rituximab. Although the association differs by indication and treatment regimen, thorough understanding of the role of Fc-gamma receptor genetic variation in determining the efficacy of ofatumumab is warranted. The evaluation summarized in this document is the first step towards understanding the role of Fc-gamma genetic variation in ofatumumab efficacy, and will be strengthened by data from additional clinical studies in the ofatumumab program. Objective: Determine if FCGR3A V158F and FCGR2A H131R are associated with ofatumumab efficacy as measured by progression-free survival (PFS) and overall response rate (ORR) in previously untreated CLL patients treated with ofatumumab in combination with chlorambucil.Research Methods: DNA samples for which PGx consent was provided were genotyped using a Taqman assay to generate FCGR3A rs396991 V158F genotypes, which were validated using Sanger sequencing. The Affymetrix Axiom Biobank whole-genome array with added custom content was used to generate genotypes for FCGR2A rs1801274 H131R and the remaining data banked for future consideration. This data was generated through a fee-for-service agreement by Biostorage Technologies Inc., 2910 Fortune Circle West, Suite E, Indianapolis, Indiana 46241 USA.Data Analysis Methods: Hardy-Weinberg equilibrium (HWE) analysis was conducted using the ethnic group with the largest sample size (self-reported non-Hispanic white). Linkage disequilibrium (LD) analysis was also conducted to evaluate the association between FCGR3A V158F rs396991 and FCGR2A H131R rs1801274. The genetic effects were evaluated in each treatment arm separately. A subgroup analysis in the self-reported non-Hispanic whites was performed as well. Statistically significant covariates were selected by step-wise variable selection while maintaining the main genetic effect in the model. A Cox proportional hazard model was used to estimate the genetic effect of FCGR3A V158F rs396991 and FCGR2A H131R rs1801274 on PFS and corresponding 95% confidence interval (CI). Logistic regression was used to assess the genetic effect on ORR. Treatment effects, measured as PFS or ORR, were also estimated within each genotype group for each marker. Analyses were performed on the independent reviewers assessed dataset as well as the investigator assessed dataset.