Background: Glutamine utilization is a metabolic pathway upregulated in renal cell carcinoma (RCC) and important for RCC tumor cell proliferation and survival. CB-839 is a first-in-class, potent, oral inhibitor of the mitochondrial enzyme glutaminase (GLS) that controls a critical step in tumor cell utilization of glutamine. In preclinical RCC models, CB-839 demonstrated synergistic anti-tumor activity when combined with cabozantinib, a VEGFR/MET inhibitor. A phase 1 study cohort of CB-839 plus cabozantinib as 2L+ therapy showed encouraging safety and efficacy results, with 40% overall response rate (ORR; RECIST v1.1) and 100% disease control rate in patients with clear cell advanced/metastatic RCC (mRCC). These findings prompted the initiation of a randomized phase 2 study comparing CB-839 plus cabozantinib vs. placebo plus cabozantinib in patients with clear cell mRCC. Methods: This international, randomized, double-blind, placebo-controlled, multi-center study (NCT03428217) will enroll ~300 patients with clear cell mRCC. Eligible patients will have received 1-2 prior lines of systemic therapy for mRCC including ≥1 anti-angiogenic therapy or the combination of nivolumab + ipilimumab. Other eligibility criteria include KPS ≥70%, measurable disease (RECIST v1.1), and no prior cabozantinib (or other MET inhibitor). Patients will be randomized 1:1 to receive CB-839 (800 mg twice daily per oral [PO] route) or placebo in combination with cabozantinib (60 mg daily PO) in 28-day cycles until disease progression or unacceptable toxicity. Patients will be stratified by prior PD-1/PD-L1 inhibitor therapy (Y/N) and IMDC prognostic risk group (favorable vs intermediate vs poor). The primary endpoint is progression-free survival (PFS; RECIST v1.1) by blinded independent radiology review; secondary endpoints are investigator-assessed PFS and overall survival. Safety, disease responses per RECIST, and quality of life will also be assessed. This important study will contribute to understanding the efficacy and safety profile of CB-839, a first-in-class metabolic inhibitor, in combination with cabozantinib in patients with mRCC. Clinical trial information: NCT03428217