49: A randomized trial of radium-223 (Ra-223) dichloride and cabozantinib in patients (pts) with advanced renal cell carcinoma (RCC) with bone metastases (RADICAL / Alliance A031801)

Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a vascular endothelial growth factor (VEGF) receptor and MET kinase inhibitor, has improved survival in pts with RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has prolonged survival in men with advanced prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition in pts with RCC and bone metastases and demonstrated safety and declines in markers of bone formation and resorption. Given that decreasing rates of SSEs and improving outcomes are unmet needs in pts with RCC and bone metastases, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in pts with RCC with bone metastases.

Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥1 metastatic bone lesions untreated with prior radiation therapy and any number of lines of prior therapy. Pts with non-clear cell RCC are eligible (capped at 20% of accrual). Pts must have a Karnofsky performance status of ≥60% and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg to be escalated to 60 mg daily after cycle 1 (1 cycle=28 days) if there is no persistent grade 2/≥3 toxicity. Ra-223 is administered at a fixed dose of 55 kB/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis.