The primary objective of this study is to compare the progression-free survival (PFS) of participants treated with telaglenastat and everolimus versus placebo and everolimus for advanced or metastatic clear cell renal cell carcinoma (ccRCC) previously treated with the following:

• At least 2 lines of therapy, including at least 1 vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI)
• Radiographic progression of metastatic RCC must have occurred (per investigator assessment) on or after the most recent systemic therapy and within 6 months prior to cycle 1 day 1

Inclusion Criteria:

• Karnofsky Performance Score (KPS) ≥ 70%

• Estimated Life Expectancy of at least 3 months

• Documented histological or cytological diagnosis of renal cell carcinoma with a clear-cell component.

• Measurable Disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the Investigator

• Must have received at least two prior lines of systemic therapy, including at least one VEGF TKI (e.g., sunitinib, sorafenib, pazopanib, cabozantinib)

  a) Radiographic progression of mRCC must have occurred (per investigator assessment) on or after the most recent systemic therapy and within 6 months prior to Cycle 1 Day 1 (C1D1).

• Prior treatment with other anti-cancer therapies including cytokines, monoclonal antibodies, immunotherapies, and cytotoxic chemotherapy is allowed

Exclusion Criteria:

• Prior treatment with mammalian target of rapamycin (mTOR) inhibitors (everolimus or temsirolimus) or CB-839

• Receipt of any anticancer therapy within the following windows before randomization:

  • TKI therapy within 2 weeks or 5 half-lives, whichever is longer
  • Any type of anti-cancer antibody within 4 weeks
  • Cytotoxic chemotherapy within 4 weeks
  • Investigational therapy within 4 weeks or 5 half-lives, whichever is longer
  • Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible.

• Unable to receive medications orally (PO) or any condition that may prevent adequate absorption of oral study medication

• Major surgery within 28 days prior to randomization

• Patients with active and/or untreated central nervous system (CNS) cancer are not eligible. Patients with treated brain metastasis must have 1) documented radiographic stability of at least 4 weeks duration demonstrated on baseline contrast-enhanced CNS imaging (eg contrast-enhanced magnetic resonance imaging [MRI] of the brain) prior to randomization and 2) must be symptomatically stable and off steroids for at least 2 weeks before randomization.

• Requirement for continued proton pump inhibitor after randomization

• Chronic treatment with corticosteroids or other immunosuppressive agents except (i) inhaled or topical steroids or replacement dose corticosteroids equivalent to ≤ 10 mg prednisone and (ii) patients receiving physiological doses of hydrocortisone for adrenal insufficiency

Double blinded, placebo-controlled