Dynamic-contrast enhanced MRI as a BAY 43-9006 marker

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DESCRIPTION (provided by applicant): Sorafenib (BAY 43-9006) was developed as an oral raf-kinase inhibitor, but additional studies have shown it to also be a potent inhibitor of VEGFR2 and PDGFR and that its principal mechanism of action in vivo is antiangiogenic. Sorafenib has shown activity in a phase II randomized discontinuation study in patients with metastatic renal cell cancer. Other phase I and phase II data show that toxicities increase with dose, but that toxicity as well as pharmacokinetics are all highly variable. There is thus an ultimate need for a biomarker to determine the best dose and to predict patient benefit with sorafenib treatment. Studies with other VEGFR and PDGFR inhibitors suggest that dynamic contrast enhanced MRI (DCE-MRI) is a useful pharmacodynamic marker and may be predictive of drug benefit. Therefore it is hypothesized that DCE-MRI is a pharmacodynamic marker for sorafenib as well. This hypothesis will be tested in a randomized clinical trial in which patients with clear cell renal cancer are assigned to therapy with placebo, low dose, or high dose sorafenib. The primary endpoint of the trial is the change in K-trans from DCE-MRI images obtained before and after 4 weeks of therapy. The area under the contrast concentration versus time curve for the first 60 seconds (AUC60) and the distribution of both parameters across all voxels of the region of interest will also be evaluated. Patients initially assigned to placebo will then be randomized a second time to low or high dose sorafenib therapy and will undergo a third DCE-MRI after 4 weeks of investigational therapy. Data from all 66 enrolled patients will then be used in secondary analyses to determine if K-trans or AUC60 correlates with steady state concentration of sorafenib or its metabolites. If the proposed preliminary trial confirms that DCE-MRI is a pharmacodynamic marker for sorafenib, future clinical trials determining whether DCE-MRI is predictive of sorafenib benefit will be undertaken.