Dose finding study of CBM588 in combination with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma: A phase I study.

TPS611 Background: The combination of nivolumab and ipilimumab is currently one of the standard-of-care treatments for patients with metastatic renal cell carcinoma (mRCC). However, in the vast majority of patients, disease progression eventually occurs. Thus, novel methods to increase the efficacy of nivolumab/ipilimumab are being explored. Recent evidence suggests that the gut microbiome can remarkably influence the efficacy of immune checkpoint inhibitors (ICI) in patients with mRCC, particularly through the modulation of microbial diversity and the presence of key bacterial species (Routy et al . Science 2018; Salgia et al . Eur Urol 2020). The current study explores the use of CBM588, Clostridium butyricum MIYARI588, which has demonstrated the potential to enhance clinical outcomes when combined with ICI therapy (Dizman et al . Nature Medicine 2022; Ebrahimi et al . Nature Medicine 2024). This ongoing phase I study aims to determine the maximum tolerated dose (MTD) of CBM588 in combination with nivolumab/ipilimumab in previously untreated mRCC patients, and to evaluate the biological effects of CBM588. Methods: This investigator-initiated, phase I, open-label, single-arm, dose-escalation study is being conducted in patients with untreated, histologically confirmed mRCC. Eligible patients must be ≥18 years old, have an ECOG performance status ≤2, and be diagnosed with clear cell and/or sarcomatoid histology. The study is open to all IMDC risk groups. Patients must have measurable disease by RECIST 1.1 and no prior systemic therapy for metastatic disease. The study follows a 3+3 dose-escalation design with three planned dose levels for CBM588 (4 × 10 8 CFU, 1.2 × 10 9 CFU, and 4 × 10 9 CFU), administered twice daily orally. Nivolumab (3 mg/kg every 3 weeks for four cycles, followed by 480 mg every 4 weeks) and ipilimumab (1 mg/kg every 3 weeks for four cycles) are administered intravenously. The primary objective is to assess the safety and tolerability with escalating doses of CBM588 in combination with nivolumab and ipilimumab. Secondary objectives include evaluating changes in the gut microbiome, modulation of immune pathways, alterations to the systemic metabolome, and clinical outcomes such as overall response rate (ORR) and progression-free survival (PFS). Responses are assessed by CT every 12 weeks. Dose level one has been completed without dose-limiting toxicities. Enrollment at dose level two began in October 2024. Clinical trial information: NCT06399419 .