Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors

Abstract

Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

Pharmacodynamic monitoring of BAY 43‐9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells

“…Pharmacokinetic data from previous clinical trials of BAY 43-9006 show that peak drug concentrations are typically in the range of 5-20 mM at the dose schedules used in the AML/MDS trial (14,20). Although these levels greatly exceed the IC50 for inhibition of raf kinase in cell-free assays and are growth-inhibitory in tissue culture experiments (12), the free concentration of BAY 43-9006 in the peripheral blood is much lower due to strong protein binding.…”

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

“…Although sorafenib is undergoing phase I/II clinical evaluation for treatment of prostate cancer [16][17][18][19][20], the apoptotic pathways and the changes in biomarker expression resulting from sorafenib treatment have not been studied. Thus, the aim of this study was to investigate the effects of sorafenib on androgen-independent prostate cancer cell viability in vitro.…”

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

“…Importantly, phase I clinical trials have demonstrated that this dose range is achievable in vivo. 18 We have previously reported that CLL cells derived from ZAP70-positive patients are significantly better protected from cytotoxic agents compared with leukemic cells from ZAP70-negative patients. These differences are based on variations of the expression of BH3 proteins between these subgroups.…”