Background: CB-839 is a selective inhibitor of GLS, a key enzyme in the utilization of glutamine by many cancer cells. CB-839 has broad activity in preclinical models, including RCC where GLS is highly expressed. In RCC cell lines, CB-839 combines synergistically with E in vitro and in vivo, strongly inhibiting cell growth as well as glucose and glutamine metabolism. Previously reported data from this study have demonstrated that CB-839 achieved robust GLS inhibition in blood and tumors at well tolerated doses and that BID dosing with meals provided optimal PK and tolerability. Methods: CX-839-001 is an ongoing Phase 1 study evaluating the safety, PK, PD and efficacy of CB-839 in advanced/metastatic cancer patients. After completing an all-comers dose escalation of monotherapy CB-839, an RCC expansion cohort (n = 11) was opened to evaluate the efficacy of monotherapy CB-839 and was further expanded after achieving a preplanned overall response rate. In addition, the combination of CB-839 with standard E (10 mg po QD; CBE) is also being studied in RCC patients, with dose escalation ongoing (3+3 design; 400 mg BID starting dose) and two expansion cohorts for clear cell and papillary RCC planned (n = 9 each). Results:Monotherapy: Safety data from 75 pts who received 600-1000 mg BID revealed a low rate of CB-839-related Gr3/4 AEs (4/75 pts). Nineteen heavily pretreated (median of 3 prior therapies) RCC pts (10 clear cell, 6 papillary, 3 other) have been enrolled on the BID dosing regimen. One pt with RCC has achieved a confirmed Partial Response (PR) that remains ongoing after 8.3 months on therapy. Radiographic Stable Disease (SD) or PR was observed in 9 of 15 (60%) efficacy-evaluable RCC pts. Duration of clinical benefit in pts with SD or better ranged between 2.1 and 8.3+ mo (median of 4.6 mo). CBE combination: Eight pts have initiated treatment with escalating doses of CB-839 (400 – 600 mg) in combination with E to date. Conclusions: Monotherapy CB-839 has been well tolerated and demonstrated evidence of efficacy in a subset of patients, including an ongoing confirmed PR, which has resulted in further expansion of this cohort. The combination of CB-839 with E is being studied. Clinical trial information: NCT02071862