A phase I/II study of sitravatinib (MGCD-516) plus nivolumab in patients (pts) with metastatic clear-cell renal cell carcinoma (ccRCC) that progressed on prior VEGF-targeted therapy.

Abstract

TPS708 Background: Sitravatinib is a potent oral tyrosine kinase inhibitor that targets multiple receptor tyrosine kinase pathways including the vascular endothelial growth factor (VEGF), c-MET, and the Tyro3, Axl, and MER family. These pathways can allow tumor cells to escape immune surveillance despite immune checkpoint therapy. We therefore hypothesized that combining sitravatinib with the anti-PD1 antibody nivolumab will enhance antitumor immune responses in pts with ccRCC. The present study is designed to determine the optimal dose for this combination using efficacy and toxicity as co-primary outcomes. Methods: This phase I/II trial uses the sequentially adaptive late-onset EffTox design (Jin et al. J Am Stat Assoc 2014), which accounts for potential late-onset toxicities induced by immunotherapy, and allows dose-finding based on both the efficacy and toxicity of each successive dose. Eligible pts have metastatic ccRCC that progressed on prior VEGF-targeted therapy. Each pt receives initially a pre-specified daily oral dose, among 4 dose levels (60mg, 80 mg, 120 mg, 150 mg), of sitravatinib monotherapy for 2 weeks to allow the drug to reach a pharmacokinetic steady state. Nivolumab is then added at the dose of 240 mg intravenously every 2 weeks. A maximum of 60 pts will be treated in up to 20 cohorts of 3 pts each. Tumor biopsies and peripheral blood are collected to assess changes in tumor microenvironment and immune markers at 4 different time points: 1) at baseline, up to 14 days prior to initiation of sitravatinib, 2) following 2 weeks of sitravatinib monotherapy, 3) after 2 infusions of nivolumab in combination with sitravatinib, and 4) at disease progression. The primary endpoint is optimal dose of sitravatinib based on toxicity (by week 12) and disease control rate (at week 6). Secondary endpoints include objective response rate, progression-free survival, and overall survival. At deadline for abstract submission, 4 pts have been treated on this study. Clinical trial information: NCT03015740.