Background: CB-839 is a first-in-class highly selective inhibitor of GLS, a key enzyme in the utilization of glutamine by many cancer cells. TNBC is very glutaminolytic, with high GLS expression and a high glutamate:glutamine ratio, and highly dependent on glutamine for growth. CB-839 has selective activity in most in vitro and in vivo TNBC preclinical models tested. CX-839-001 is an ongoing Phase 1 basket trial of CB-839 as monotherapy and in combination with approved agents. BID dosing of CB-839 with meals provided optimal PK and tolerability and achieved robust inhibition of GLS in blood and tumors. After achieving strong GLS inhibition with acceptable toxicity and observing a TNBC patient (pt) with a 23% reduction in tumor burden on study for >18 months, a combination arm testing CB-839 with Pac (Pac-CB) for TNBC was opened. Methods: Patients with metastatic TNBC received escalating doses of CB-839 (400-800 BID) in combination with a fixed weekly Pac dose (80 mg/kg on Days 1, 8, 15 of 28 day cycle). Upon demonstration of safety and tolerability of the 600 mg BID CB-839 dose, an expansion cohort of taxane-naïve TNBC pts was opened (n=14). Results: Twelve pts have received Pac-CB during the dose escalation; 7 pts at 400 mg BID, 4 at 600 mg BID and 1 at 800 mg BID. These patients have been heavily pretreated (3 median prior therapies for adv/met disease), including 7 pts that have received a prior taxane (3 in the adv/met setting). The combination has been well tolerated with only one DLT to date (G4 neutropenia at 400 mg BID). Among 11 efficacy-evaluable TNBC pts on the Pac-CB treatment, 2 pts have achieved partial response (PR) and 4 pts have achieved stable disease (SD). Both pts with PRs had received prior Pac, including one pt that progressed on Pac without achieving a response. Three of the 4 SD pts remain on study for 2.9+, 7.1+, and 8.8+ months. Conclusions: The Pac-CB combination has been well tolerated with only 1 DLT to date; expansion at the CB-839 dose of 600 mg BID is in progress. Preliminary activity has been demonstrated with 2 PRs in the first 8 pts enrolled, even in the setting of prior progression on paclitaxel. Updated data on the expansion cohort will be presented. Clinical trial information: NCT02071862