Background: Glutamine is required for the growth and survival of multiple tumor types. CB-839 is a highly selective, reversible, allosteric inhibitor of glutaminase, a choke point in the utilization of glutamine. CB-839 has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies. Methods: CX-839-001 is an ongoing Phase 1 study of escalating doses of CB-839 in advanced and/or treatment-refractory solid tumor patients (pts) to evaluate safety and tolerability, and to identify the recommended Phase 2 dose (R2PD). CB-839 was administered orally continuously in 21-day cycles. Pharmacokinetics (PK) was monitored on Days 1, 15, and 22; pharmacodynamic (PD) assessment of glutaminase activity was measured ex vivoin platelets and tumor biopsies. Additional pts will be enrolled at the RP2D with triple negative breast cancer (TNBC), non-small cell lung adenocarcinoma (NSCLC), renal cell carcinoma (RCC), mesothelioma, and tumors with mutations in enzymes of the TCA cycle. Results: 35 pts were enrolled in dose escalation receiving CB-839 doses from 100 to 800 mg TID and 600 mg BID. Exposure increased less than dose proportionally but there was a clear PK/PD relationship with > 90% glutaminase inhibition in platelets when CB-839 exceeded 450 nM; target inhibition was confirmed in tumors. Radiographic stable disease (SD) was observed in 7 (28%) of 25 efficacy-evaluable pts (average duration 107 days; range 59-209) across all diseases and dose levels including TNBC (2/9 evaluable pts), NSCLC (2/4), mesothelioma (2/4) and RCC (1/3). Grade ≥ 3 treatment-related AEs occurred in 7 (20%) of pts, including ALT/AST (4 pts), creatinine, alkaline phosphatase, and GGT increases, lymphopenia, and hypoglycemia (1 pt each). A Grade 3 increase in creatinine considered unlikely related to CB-839 was a DLT at 250 mg TID. CB-839 was absorbed rapidly (T_max 1-2 hr fasted and 2-4 hr fed) and cleared with a half-life of about 4 hr. Plasma C_minwas > 450 nM at steady state at the RP2D of 600 mg BID. Conclusions: Continuous CB-839 administration showed an acceptable safety profile, significant glutaminase inhibition and preliminary signs of clinical activity in multiple tumor types. Clinical trial information: NCT02071862