Background: Colorectal cancers (CRCs) harboring a PIK3CA mutation demonstrate glutamine dependency in both in vitro and in vivo models, including those known to be fluoropyrimidine (FP) resistant. CB-839 (CB) is an oral inhibitor of glutaminase, a key enzyme in glutamine metabolism. Preclinical studies further show that the combination of CB and a FP is superior to either as a single agent, and can overcome FP resistance. We conducted a phase I trial to assess the maximum tolerated dose and dose limiting toxicities (DLTs) of CB when given with capecitabine (C). Methods: Patients with advanced solid tumors and disease progression on standard treatment, or for whom C is an acceptable treatment option, were enrolled. A standard 3+3 design was used to assess escalating doses of CB (400-800 mg) and C (750-1000 mg/m²) in four dose levels. CB was given orally twice daily continuously and C was given orally twice daily on days 14/21 of a 21 day treatment cycle. DLT period was 21 days. Restaging CT scans were obtained every 9 weeks with response assessment per RECIST. Adverse events were assessed per CTCv4. Results: 16 patients were enrolled: 38% male, 94% white, 6% African American, median age 69.5 years (43-80), mean number of cycles 7.3 (1-11). Seven patients were treated at the final dose level (CB 800 mg and C 1000 mg/m²) and no DLTs were observed. Grade 3 adverse events included elevated ALT (n = 1), elevated AST (n = 1), anorexia (n = 1), decreased lymphocytes (n = 1), palmar-plantar erythrodysesthesia (n = 3), diarrhea (n = 1) and vomiting (n = 1). Grade 4 AEs included decreased lymphocytes (n = 1). Ten patients achieved stable disease as their best response, 9 being FP resistant. Associated median progression free survival (PFS) was 16.5 weeks among all patients (n = 16) and 29.5 weeks in PIK3CA mutant CRC patients (n = 6). At this time 2 patients remain on treatment at 31 and 3 weeks. Conclusions: CB 800 mg may be safely administered with C 1000 mg/m² with minimal toxicity. While no RECIST response was observed, several patients with prior FP resistance experienced prolonged PFS, particularly patients with PIK3CA mutant CRC. The phase II portion of this study in patients with PIK3CA mutant CRC is pending. NCT02861300, 2P50CA150964-06A1 Clinical trial information: NCT02861300