Dual VEGF/VEGFR inhibition in advanced solid malignancies: Clinical effects and pharmacodynamic biomarkers

摘要: Our prior phase I study of the combination vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion this was thus undertaken to obtain further safety data, assessment characterization pharmacodynamic biomarkers melanoma, renal, adrenal carcinoma patients. Patients with metastatic received sunitinib (37.5 mg/d, 4 wk on/2 off) bevacizumab (5 mg/kg intravenously every 2 wk). Responses were assessed cycles. Serum levels angiogenic molecules measured using ELISA assays. Twenty-two patients enrolled, including 11 5 renal cell (RCC), cancer, 1 angiosarcoma. Grade 3 or higher adverse events observed 15 patients, hypertension (41%), thrombocytopenia (23%), fatigue (14%). Three RCC melanoma patient developed thrombotic microangiopathy (TMA). Partial (PR) occurred 21% (2), (1), (1) carcinomas. Overall, 6 demonstrated some reduction their tumor burden. several other proangiogenic proteins declined over first treatment whereas putative VEGF-resistant protein, prokineticin-2, increased 10-fold. Occurrence TMA related dual VEGF/VEGFR inhibition can result from systemic nephron specific injury even non-renal malignancies. While clinically efficacious observance microangiopathy, non-RCC is a significant toxicity that precludes clinical development.