ICON trial: Phase I/II trial of inulin gel in combination with ipilimumab and nivolumab in advanced renal cell.

Abstract

TPS572 Background: The gut microbiome has been shown to impact the safety and efficacy of immune checkpoint inhibitor (ICI) therapy. Fecal microbiota transplantation and probiotics such as Clostridium butyricum have demonstrated promise in enhancing ICI efficacy. Inulin is a plant-derived prebiotic dietary fiber found in chicory root and Jerusalem artichoke that increases levels of Bifidobacterium in the gut. Native inulin undergoes rapid degradation and absorption in the upper GI tract, failing to adequately reach beneficial microbes residing in colon. To address this limitation, we developed a colon-retentive inulin-gel oral formulation. In murine models, our inulin gel significantly enhanced systemic anti-tumor efficacy of αnti-PD-1 therapy and led to decreased rates of immunotherapy induced colitis. A study in healthy volunteers established the tolerability of inulin gel. Based on preclinical data demonstrating enhanced ICI efficacy and favorable clinical tolerability, this clinical trial was designed to evaluate the combination of inulin gel with ipilimumab and nivolumab in patients with advanced clear cell renal cancer. Methods: After an initial safety run-in of 6 patients receiving the combination, patients will be randomized 2:1 to the combination of ipilimumab 1mg/kg + nivolumab 3mg/kg (ipi-nivo) and inulin gel 10g twice daily vs ipi-nivo standard of care therapy. Eligible patients have advanced clear cell or sarcomatoid RCC with no prior systemic anticancer therapy. Adjuvant pembrolizumab is permitted if completed > 6 months prior to study enrollment. Patients must be candidates for ipi-nivo as determined by their treating physician. Performance status of 0-1 and adequate bone marrow, renal and liver function are required. The primary endpoint is the proportion of patients free of progression at 6 months. Secondary endpoints include response rate, overall survival, and incidence of immune related and other toxicities. Correlative objectives include assessment of liquid biopsy and baseline tissue genomic sequencing for prognostic and predictive markers, measuring the change in short chain fatty acid levels in stool and changes in the microbiome. Quality of life will be evaluated by patient reported surveys. We anticipate enrollment of 48 patients. The sample size is not sufficiently large to do a formal hypothesis test between the two randomized arms in the study. We will instead provide a confidence interval for the difference in the response rate and progression free survival between the two arms. The analysis will provide the preliminary data required to consider moving towards a larger randomized trial. Clinical trial information: NCT06866262 .