Phase I Trial of Dabrafenib and Pazopanib in BRAF Mutated Advanced Malignancies

PurposeSeveral tumor types carry BRAF mutations and vascular endothelial growth factor pathway upregulation. Resistance mechanisms to BRAF inhibitors can include platelet-derived growth factor-β upregulation. Dabrafenib, a BRAF inhibitor, and pazopanib, a multikinase inhibitor that targets vascular endothelial growth factor and platelet-derived growth factor, have not been combined previously. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the combination.Patients and MethodsPatients with any advanced BRAF mutated malignancy with adequate organ function were eligible. Prior use of dabrafenib or pazopanib was not allowed. Dosages started at dabrafenib 50 mg twice a day and pazopanib 400 mg daily on dose level (DL) 1, with maximum dosages of 150 mg twice a day and 800 mg daily on DL5. Pharmacokinetics and BRAF V600E plasma clone were measured, and efficacy was evaluated by imaging and tumor markers every 8 weeks.ResultsTwenty-three patients with 11 differen...