Phase II trial of combination nab -paclitaxel, carboplatin and gemcitabine in first line therapy of advanced urothelial carcinoma

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.