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Proposal 1128

Title of the Proposed Research

EuroTARGET GWAS on sunitinib pharmacogenetics in patients with metastatic renal cell carcinoma.

Lead Researcher

Prof. H.J. Guchelaar

Affiliation

Leiden University Medical Center (LUMC)

Funding Source

Financial support: This research is supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259939.
This research is supported by Pfizer and GSK..

Potential Conflicts of Interest

None

Data Sharing Agreement Date

14 November 2016

Lay Summary

Sunitinib is the first-choice treatment for metastatic renal cell carcinoma (mRCC) and has a wide inter-individual variability in pharmacokinetics (PK) and pharmacodynamics. Therefore, we are not yet able to predict the individual treatment outcome on sunitinib. Studies using the candidate gene approach identified Single Nucleotide Polymorphisms (SNPs) in genes related to the PK and pharmacodynamics of sunitinib to be associated with toxicity and efficacy. A Genome-Wide Association Study (GWAS) will be more informative by testing >1 million SNPs and using a hypothesis-free approach ensuing a better understanding on biological mechanisms underlying the effects of SNPs on sunitinib response. To date, no GWAS on sunitinib pharmacogenomics has been published yet. We have set up a European collaborative project on "TArgeted therapy in Renal cell cancer: GEnetic and Tumour related biomarkers for response and toxicity" (EuroTARGET). The objective is to identify germline genetic variants that associate with sunitinib efficacy and toxicity in mRCC patients using a 2-step GWAS approach on a retrospective discovery cohort and a prospective validation cohort. Subjects diagnosed with mRCC receiving sunitinib in medical centers in Europe, the USA and Japan are included. DNA samples have to be available. For discovery analysis, patients were divided into two cohorts with Caucasians (discovery cohort I) and Asians (discovery cohort II) and also for validation analyses (validation cohort I:Caucasians and validation cohort II:Asians). Genotyping was performed using the HumanOmniExpress BeadChip (Illumina) and the Illumina Human Omni5 array. Toxicity and efficacy data were obtained by a review of the medical record of each patient and scored according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE). The primary outcome measure for efficacy analysis was PFS, defined as the time in months between the first day of sunitinib treatment and the date of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST). In addition associations between SNPs and OS were tested. Statistical analyses were performed using PLINK software, version 1.07. For discovery GWAS analyses, SNPs and covariates will be tested for their influence on the outcome with a significance threshold of p<0.1. Cumulative dose will also be included as a time-dependent covariate. Multivariately, SNPs and covariates for safety analysis will be tested for association with toxicities and dose reductions using binary logistic regression. SNPs and covariates for efficacy analysis will be tested for association with PFS, OS and response rate using cox-regression analysis with inclusion of covariates using the additive genetic model. Associations with a p-value =5*10-8 were considered significant. The top hits of the VEG116087 (PGx420 study) will be tested in the validation set. Results will be presented as OR/HR and 95% CIs and p-values

Study Data Provided

GSK-VEG108844: Study VEG108844, A study of Pazopanib versus Sunitinib in the Treatment of Subjects with Locally Advanced and/or Metastatic Renal Cell Carcinoma

Statistical Analysis Plan

Publication Citation

The publication citation will be added after the research is published.

Summary Results

Results summary or link will be posted when available.