Phase I trial of dabrafenib and pazopanib in BRAF mutated advanced malignancies

Purpose Several tumor types carry BRAF mutations and vascular endothelial growth factor pathway upregulation. Resistance mechanisms to BRAF inhibitors can include plateletderived 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 Methods Patients 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. Results Twenty-three patients with 11 different tumor histologies were enrolled in five DLs. Two dose-limiting toxicities were observed-a grade 3 bowel perforation on DL3 and grade 3 arthralgia on DL5. Common drug-related adverse events included nausea (52%), skin papules (43%), diarrhea (39%), hand-foot syndrome (30%), anemia (26%), rash (22%), vomiting (22%), hypophosphatemia (22%), and transaminitis (22%). Five patients (22%) experienced a partial response, including low-grade ovarian serous carcinoma, thyroid cancer, and glioblastoma multiforme, and two patients (appendiceal and thyroid cancer) had stable disease > 6 months. Pharmacokinetic measurements revealed pazopanib levels < 17.5 μg/mL in 80% of treated patients at steady state, particularly at DL5. BRAF V600E plasma copies correlated with response and progression. Conclusion Combination dabrafenib and pazopanib had no unexpected toxicities, and durable partial responses were observed at DL3 or greater. Dose escalation beyond DL5 may be considered as pazopanib levels were suboptimal as a result of drug interaction with dabrafenib.