PGX7550: PGx Investigation of Pyrexia by Meta-Analysis of Dabrafenib/Trametinib Melanoma Studies BRF113710, BRF113929, BRF113683 and MEK115306

Trial description: Dabrafenib (GSK2118436) is a potent, ATP-competitive and selective inhibitor of mutant BRAF kinase (V600E/K) and trametinib (GSK1120212) is a selective, non-ATP competitive, allosteric inhibitor of MEK1 and MEK2 kinases. The U.S. Food and Drug Administration recently approved dabrafenib and trametinib as single-agent therapies as well as in combination for the treatment of unresectable melanoma or metastatic melanoma in adult patients with the most common type of BRAF mutations: BRAF V600E (dabrafenib) and BRAF V600E/K (trametinib). The BRAF V600E/K mutation is found in 40-60% of melanomas causing constitutive activation of BRAF and, in turn, the MAP kinase pathway.Pyrexia, or fever, is one of the most common adverse events (AE) in subjects exposed to dabrafenib, and is observed in up to 1/3 of subjects receiving this drug. The incidence of pyrexia is much higher (up to 70%) in subjects treated with a combination of dabrafenib and trametinib. The majority of these AEs are transient and resolve after treatment interruption, while a small proportion (2-5%) of subjects develops serious non-infectious febrile events such as influenza-like illness, cytokine release syndrome, and systemic inflammatory response syndrome which may require extensive management. The underlying mechanism for development of pyrexia on treatment with dabrafenib alone or in combination with trametinib is not clear. A prior PGx investigation of pyrexia (BRF116604) in 3 dabrafenib melanoma studies (BRF113710, BRF113929 and BRF113683) identified an association trend (p<0.05) of a functional variant in IL28B with pyrexia. The primary objective of this study is to further follow up previously identified suggestive associations between pyrexia and the genetic variant in IL28B (rs8099917) by meta-analysis of melanoma subjects from BRF113710, BRF113929, BRF113683 and MEK115306. The exploratory objectives are to investigate other genetic associations (candidate gene and genome wide) with pyrexia by meta-analysis of subjects from BRF113710, BRF113929, BRF113683 and MEK115306. PGx subjects from MEK115306 (n=380) will be genotyped for all markers on the Affymetrix Axiom® Biobank plus GSK Custom array panel. After genotype QC, approximately 650K SNPs across the genome, are expected to be available for analysis. While all 650K markers will be used for Principal Component Analysis to characterize the genetic ancestry of the PGx population, the following markers will be selected and stratified into tiers for genetic association analysis with the study endpoints:Tier I: IL28B candidate gene variant. Tier II: Functional polymorphisms in 29 candidate genes (N=60). Tier III: Genome-wide imputed variants (N=10,000,000 variants in total). Meta-analysis will be conducted on subjects from four metastatic melanoma studies (BRF113710, BRF113929, BRF113683 and MEK115306). The subjects from BRF113710, BRF113929, BRF113683 (BRF116604) will be re-analyzed in genome-wide imputed data. The two arms (dabrafenib monotherapy and a combination of dabrafenib and trametinib) in MEK115306 will be analyzed independently using a logistic model with gender and the first top 10 principal components and meta-analyzed with results from BRF116604. Overall, 132 and 275 subjects meet the strict definition of case and control, respectively. Genotype association tests will be performed assuming an additive genetic model.AXIOM is a registered trademark of AFFYMETRIX, INC.