RENAVIV: A randomized phase III, double-blind, placebo-controlled study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma.

Abstract

TPS681 Background: Abexinostat is a pan-histone deacetylase (HDAC) inhibitor that has shown promising activity in prior pre-clinical studies and early phase clinical trials. A phase 1b study of pazopanib plus abexinostat (Aggarwal et al. J Clin Oncol 2017) demonstrated strikingly durable responses in patients (pts) with clear cell renal cell carcinoma (RCC), including one patient with previously refractory disease with ongoing response for > 5 years’ duration. Induction of histone acetylation in peripheral blood mononuclear cells (PBMCs) was associated with durable treatment response. We hypothesize that the addition of abexinostat to pazopanib will significantly improve outcomes in patients with clear cell RCC. Methods: RENAVIV is a global, randomized, double-blind, placebo-controlled, two arm phase 3 study of pazopanib plus abexinostat versus pazopanib plus placebo, in pts with locally advanced or metastatic RCC with clear cell component. Up to one prior line of immunotherapy is allowed. Prior VEGF-targeting tyrosine kinase inhibitor treatment is prohibited. Stratification factors include: 1) Prior immunotherapy (yes/no) and 2) prognostic group (good, intermediate, poor). Pts randomized to pazopanib + placebo have the option of crossing over to receive pazopanib plus abexinostat at the time of disease progression. The primary endpoint is PFS by independent review committee. Secondary endpoints include PFS by investigator assessment, overall survival, safety, objective response rate (ORR), duration of response, patient-reported quality of life, and outcomes in cross-over population. Planned correlative studies include association between histone acetylation and HDAC expression in PBMCs with clinical outcomes. The total planned accrual is 413 pts, estimated to provide 90% power to detect a hazard ratio of 0.67 in the comparison of PFS between experimental versus control arms, with an overall two-sided type I error rate of 0.025. A pre-specified minimum of 50% of patients are required to have received prior immunotherapy. The first patient was enrolled in October 2018. Clinical trial information: NCT03592472.