BACKGROUND Paclitaxel has significant single agent activity in urothelial cancer. The 130 nm albumin bound paclitaxel (nab-paclitaxel, ABI-007) delivers more paclitaxel to tumor than conventional paclitaxel without cremophor related toxicities. We assessed the efficacy of nab-paclitaxel in combination with carboplatin and gemcitabine as first line therapy in advanced urothelial cancer. METHODS Eligible patients had histologically confirmed metastatic, locally recurrent or advanced pure or mixed urothelial cancer, ECOG performance status of 0-2, no prior chemotherapy for current disease stage and no taxane for ≥ 1 year. Therapy consisted of nab-paclitaxel at 220 mg/m2 intravenously with optional dose escalation to 260 mg/m2 for subsequent cycles, with carboplatin AUC 5 on day 1 and gemcitabine at 800 mg/m2 on days 1 and 8 in 21-day cycles. Dose modifications in all three drugs to -1 and -2 levels were allowed for toxicity. Primary endpoint was overall response rate by RECIST 1.0. Secondary endpoints were safety, progression free and overall survival. Using a two-stage design, 32 patients were planned to be enrolled. RESULTS Due to poor accrual only 16 patients were enrolled. Thirteen patients had metastatic disease, 3 were women, and median age was 73.9 years (range 51.3-83). ECOG PS was 0 in 4 (25.0 %) and 1 in 11 (68.8 %) patients. Creatinine clearance by Cockroft-Gault formula was less than 60 in 43 % of patients and 50 % of patients had visceral disease at baseline. The regimen was associated with severe toxicity, mainly cytopenias. Adverse events required removal of 11 patients (68.8 %) from study. Seven patients (43.7 %) missed ≥ 1 dose due to toxicity and 7 patients were reduced to -2 dose level. Nine (56.4 %) grade ≥ 3 neutropenia and thrombocytopenia each but only 1 episode of febrile neutropenia (6.3 %) was reported. Grade ≥ 3 anemia was noted in 6 patients (37.5 %). Grade 2 neuropathy was seen in 12.5 % but no grade ≥ 3 neuropathy was observed. One patient had confirmed PR (6.7 %; 95 % CI, 0-32 %) and 2 (13.3 %) had unconfirmed PR. Six other patients (40 %) had SD. Due to censoring at study exit due to adverse events before true progression, median PFS was 11.2 months (95 % CI,2.0-11.2 m). Median overall survival was 13.1 months (95 % CI, 9.8-19.6 m). CONCLUSIONS The combination of nab-paclitaxel, carboplatin and gemcitabine was poorly tolerated in this high risk patient population at these doses and schedule. Other nab-paclitaxel based combinations should be explored in first line therapy of advanced urothelial cancer.