PGx7607: PGx evaluation of pyrexia by meta-analysis of melanoma subjects from BRF113710, BRF113929, BRF113683, MEK115306 and MEK116513

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 or a combination of dabrafenib and trametinib. 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. Prior pharmacogenetics (PGx) investigations of pyrexia (BRF116604 and 200997) in melanoma studies of dabrafenib or a combination of dabrafenib and trametinib (BRF113710, BRF113929, BRF113683 and MEK115306) identified no significant associations between pyrexia and potentially functional candidate, or genome wide variants or variants from HLA genes. However, with small sample sizes, the power to identify small or moderate genetic effects in these studies was limited.The primary objective is to investigate genetic associations (genome wide) with pyrexia by meta-analysis of Caucasian subjects treated with dabrafenib or a combination of dabrafenib and trametinib from BRF113710, BRF113929, BRF113683, MEK115306 (mono and combi) and MEK116513-combi. The secondary objectives are 1) to identify genetic associations with early onset pyrexia (pyrexia developing within the first 8 weeks of treatment) by meta-analysis of Caucasian melanoma subjects treated with dabrafenib or a combination of dabrafenib and trametinib from studies BRF113710, BRF113929, BRF113683, MEK115306 (mono and combi) and MEK116513-combi. 2) to identify genetic associations with time-to-pyrexia onset by meta-analysis of subjects treated with dabrafenib or a combination of dabrafenib and trametinib from studies BRF113710, BRF113929, BRF113683, MEK115306 (mono and combi) and MEK116513-combi. Genome wide genotype data generated for previous PGx evaluations using either the Illumina Human Omni Express plus Exome (OEE) BeadChip array (BRF116604) or Affymetrix Axiom Biobank Plus GSK Custom array (200997) will be reused in this PGx investigation. Genome wide data for MEK116513 will be generated using Affymetrix Axiom Biobank Plus GSK Custom array. Genome wide imputation will be carried out to obtain missing genotype data for variants typed on the 2 genotyping platforms and to obtain genotype data for class I and II HLA gene variants. A total of 6 million genetic variants (directly genotyped or imputed) across two different genotyping platforms will be tested for association with pyrexia in a hypothesis-free genome wide association approach (GWAS). The HLA alleles (n=50) will be analyzed for associations with pyrexia.Meta-analysis will be conducted on Caucasian melanoma subjects from five metastatic melanoma studies (BRF113710, BRF113929, BRF113683, MEK115306, and MEK116513). The subjects from BRF113710, BRF113929, BRF113683 and MEK115306 were analyzed in a prior PGx investigation of pyrexia, 200997. The dabrafenib and trametinib combination arm in MEK116513 (MEK116513-combi) will be analyzed independently using a logistic model with gender and the first top 10 principal components and meta-analyzed with results from 200997. Overall, 218 and 361 subjects meet the strict definition of case and control, respectively. Genotype association tests will be performed assuming an additive genetic model.All other trademarks identified herein are the intellectual property rights of their respective owners.