Niraparib in Combination with Cabozantinib (XL184) in Patients with Advanced Urothelial Cancer (NICARAGUA)

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor. Its primary targets are Hepatocyte growth factor receptor protein (MET), vascular endothelial growth factor receptor 1-3 (VEGFR1-3), RET, AXL, FLT3 and KIT. Cabozantinib has been approved by the FDA for clinical treatment of progressive, metastatic medullary thyroid cancer. Recently published trials have demonstrated activity for cabozantinib in patients with advanced renal cell carcinoma and metastatic castration-resistant prostate cancer (mCRPC). Furthermore, in preclinical models of urothelial carcinoma (UC) of the bladder, cabozantinib has demonstrated the ability to inhibit tumor xenograft growth. It has been suggested that levels of soluble Met ectodomain (sMet) can be measured in the urine as a useful biomarker to monitor the efficacy of c-Met therapy in bladder cancer patients. Moreover, cabozantinib has demonstrated activity in heavily pretreated, advanced bladder cancer patients, with a response rate of 19.5% and manageable toxicities. In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine maximum tolerated dose (MTD) in patients with advanced urothelial or renal cell carcinoma. In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma. Efficacy results will be correlated with genomic alterations related to c-Met and Poly \[ADP-ribose\] polymerase (PARP) inhibitor activity.