Background: Glutamine metabolism is upregulated in renal cell carcinoma (RCC) and important for RCC tumor cell proliferation and survival. CB-839 is a first-in-clinic, potent, oral inhibitor of the mitochondrial enzyme glutaminase (GLS), which controls a critical step in tumor cell metabolism of glutamine. CB-839 demonstrated synergistic anti-tumor activity when combined with cabozantinib, a VEGFR2/MET/AXL inhibitor, in preclinical RCC models. In a phase 1 study cohort, CB-839 plus cabozantinib as 2L+ therapy showed encouraging safety and efficacy results, with 50% overall response rate (ORR; RECIST v1.1) and 100% disease control rate in 10 patients with clear cell advanced/metastatic RCC (mRCC). A randomized, double-blind study comparing CB-839 plus cabozantinib vs. cabozantinib plus placebo has been initiated in patients with clear cell mRCC. Methods: In this ongoing international, randomized, double-blind, multi-center study, enrollment is planned for ~300 patients with clear cell mRCC. To be eligible, patients should have received 1-2 prior lines of systemic therapy for mRCC including ≥1 anti-angiogenic therapy or the combination of nivolumab + ipilimumab, have KPS ≥70%, measurable disease (RECIST v1.1), and no prior cabozantinib (or other MET inhibitor). Patients are randomized 1:1 to receive either CB-839 (800 mg twice daily per oral [PO] route) plus cabozantinib (60 mg daily PO) or cabozantinib plus placebo in 28-day cycles until disease progression or unacceptable toxicity. Patients are stratified by prior PD-1/PD-L1 inhibitor therapy and by IMDC prognostic risk group (favorable vs. intermediate vs. poor). The primary endpoint is progression-free survival (PFS) per RECIST v1.1, determined by blinded independent radiology review. Secondary endpoints are investigator-assessed PFS and overall survival. Safety, response per RECIST, and quality of life are also assessed. Findings of this randomized, international clinical trial will inform the efficacy and safety profile of CB-839, a first-in-clinic metabolic inhibitor, in combination with cabozantinib in patients with mRCC. Clinical trial information: NCT03428217