For a study, researchers sought to understand that Telaglenastat, an investigational small-molecule glutaminase inhibitor, shows modest single-agent activity in patients with renal cell carcinoma (RCC). This phase Ib trial looked at telaglenastat combined with cabozantinib or everolimus, both of which were known to impair glucose metabolism in patients with metastatic RCC (mRCC). In a 3 plus 3 design, mRCC patients received escalating doses of telaglenastat [400–800 mg per os (p.o.) twice daily] plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; Telus). Every 8 weeks, the tumor response (RECISTv1.1) was evaluated. The primary endpoints were safety and antitumor activity. A total of 27 patients were given TelaE, and 13 were given TelaC, with a median of 2 and 3 prior therapies, respectively. The most common treatment-related adverse events were decreased appetite, anemia, elevated transaminases, diarrhea with TelaE, decreased appetite, elevated transaminases, and fatigue with Telus. Each cohort experienced 1 dose-limiting toxicity: a grade 3 pruritic rash with TelaE and thrombocytopenia with Telus. There was no MTD for either combination, so a phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C was recommended. The disease control rate (DCR; response rate + stable disease) for TelaE was 95.2% [20/21, including 1 partial response (PR)] in 21 patients with clear cell histology and 66.7% (2/3) in papillary histology. Telus DCR was 100% (12/12) across the board for both histologies [5/10 PRs as the best response (3 confirmed) in the clear cell]. TelaE and TelaC demonstrated promising clinical activity and tolerability in patients with advanced mRCC.