A phase I trial to assess the biologic effect of CBM588 (Clostridium butyricum) in combination with nivolumab plus ipilimumab (nivo/ipi) in patients with metastatic renal cell carcinoma (mRCC).

Abstract

TPS764 Background: The combination of the immune checkpoint inhibitors (ICIs) nivo/ipi is standard of care for pts with intermediate/poor-risk clear cell RCC. Although data are encouraging, less than 50% of pts will exhibit partial or complete response with nivo/ipi, and approximately 20% of pts will progress through this regimen. Studies have shown that response to ICIs may be modulated by the gut microbiome (Routy et al Science 2018), and that certain gut bacteria (e.g., Bifidobacterium spp) may predispose pts to response (Caitano et al ASCO GU 2017). CBM588 is a strain of Clostridium butyricum, a Gram-positive bacillus which produces short-chain fatty acids. It promotes the growth of commensal gut bacteria like Bifidobacterium, Lactobacillus and Bacteroides spp, and has been shown to enhance Th1 cells and IL-10 production with immunomodulatory effects. Here, we present the study design of an ongoing phase I trial to assess the biologic effect of CBM588 in combination with nivo/ipi in pts with mRCC. Methods: This is a single institution phase I trial. Pts will be randomized to one of two treatment arms. The experimental arm will receive the standard dose/schedule for nivo/ipi (3 mg/kg / 1 mg/kg Q3w for 12w, followed by nivo alone Q4w) plus CBM588 (60 mg PO 3x/d). The control arm will receive nivo/ipi at standard dose/schedule. Key eligibility criteria include intermediate/poor-risk mRCC, no concurrent antibiotic therapy and no prior systemic treatment. The primary objective is to determine the biologic effect of CBM588 + nivo/ipi in the modulation of the gut microbiome, measured by the change in Bifidobacterium spp and Shannon index (a measure of microbiome diversity). Secondary objectives include clinical efficacy (progression free survival by RECIST 1.1) and assessment of systemic immune-modulation effects through the analysis of circulating Tregs, MDSCs, and circulating cytokines/chemokines. Stool samples and serum correlatives will be collected on weeks 1 and 13 of treatment. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoints. Clinical trial information: NCT03829111.