A Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients with Advanced Renal Cell Carcinoma with Bone Metastases

National Cancer Institute (NCI)
Study Design: 
This Phase II randomized trial enrolls patients advanced RCC of any histologic subtype with at least 2 metastatic bone lesions that have not been previously irradiated. Patients may have had 2 prior lines of systemic therapy, but cannot have received cabozantinib. Prior Radium-223 dichloride treatment is also an exclusion criteria. Patients will be randomized to receive either Radium-223 dichloride every 28 days with cabozantinib 40 mg every day, or cabozantinib 40 mg every day. Patients in the combination arm will be treated with 6 treatments of Radium-223 dichloride and cabozantinib until disease progression or unacceptable toxicity; patients in the cabozantinib arm will be treated until disease progression or unacceptable toxicity.
Roughly a third of patients with metastatic RCC have bone metastases, with the prevalence higher in patients with intermediate or poor risk disease. This leads to increased morbidity in these patients due to skeletal related events (SREs), and data suggest that these patients also have decreased survival. In the Phase III METEOR trial, cabozantinib appeared to particularly benefit the subset of patients with bone metastases compared to everolimus, both in terms of clinical endpoints as well as in changes in bone turnover markers. Radium-223, an alpha emitting radioisotope and calcium-mimetic, has been shown to decrease SREs in patients with metastatic castration resistant prostate cancer. An exploratory Phase I trial of Radium-223 combined with either sorafenib or pazopanib in patients with mRCC with at least one bone metastasis demonstrated significant declines in bone turnover markers. Given these findings suggesting combination activity of tyrosine kinase inhibitors with Radium-223, and the evidence suggesting benefit of cabozantinib in patients with bone involvement, this Phase II study evaluates whether there is benefit to addition of Radium-223 to cabozantinib.
The primary endpoints of this trial is symptomatic skeletal event(SSE)-free survival of the combination of Radium-223 and cabozantinib compared to cabozantinib alone. Secondary endpoints include SSE-free survival in predefined subgroups, progression free survival (PFS), overall survival (OS), time to first SSE, toxicity and objective response rate (ORR). The effect on markers of bone turnover will be examined as a correlative endpoint.
This NCI-sponsored multi-center Phase II trial evaluates RCC patients with bone metastases, a population with poor outcomes both in terms of morbidity and mortality. Importantly, while Radium-223 dichloride has been studied alone in patients with prostate cancer and in combination with antiangiogenesis agents in patients with mRCC, this study will better evaluate whether there is a benefit to Radium-223 added to treatment. Prior studies did not have a control arm, and this study has a cabozantinib alone arm. This single-agent arm will also better characterize the outcomes of patients with osseous metastases treated with cabozantinib. With correlative analysis of markers of bone turnover in this study, there is potential to further understanding of the mechanism of the effect of both Radium-223 dichloride and cabozantinib on osseous metastases.