4753 Background: Gemcitabine and Irinotecan (Irinogem) are newer generation agents with different mechanisms of action, non-overlapping toxicity profiles, and synergistic activity in-vitro. Based on our previous laboratory data, human xenograft in-vivo models confirmed activity of Irinotecan and it’s combinations in human urothelial tumors. We are conducting a phase II trial of Irinogem to evaluate it’s efficacy and toxicity in patients with metastatic bladder cancer. Methods: Thirteen patients have been enrolled to date, of which 10 are evaluable for response. The median age is 65 years (range 55–78). According to Bajorin’s prognostic model for metastatic bladder cancer, 9 patients were classified as having 0 risk factors (KPS ≥80 with no visceral disease), and 4 patients had 1 risk factor (KPS ≥80 with visceral disease). Gemcitabine 1000 mg/m2 and Irinotecan 100 mg/m2 were administered on days 1 and 8 of each 3 week cycle. All patients had histologically proven TCC of the bladder with bidimensionally measurable disease. All but one patient were chemotherapy-naive at enrollment. Results: An average of 4 cycles were delivered per patient. Ten patients have finished therapy, while three patients are currently on treatment, with continued response. One patient was taken off therapy due to grade 4 fatigue, 1 due to stroke, 1 due to grade 4 colitis, 1 due to progressive disease, and 1 declined to participate in the trial after receiving the first cycle of therapy. Among 10 patients evaluable for efficacy, objective radiographic response was documented in 8 patients (two complete and six partial responses). The median time to progression was 8 months (range 3–11 months) among those patients who have progressed. Toxicity, evaluated in all 13 patients, was modest: 2 episodes of febrile neutropenia, grade 3–4 neutropenia in 4 patients, grade 3–4 diarrhea in 2 patients, grade 3–4 fatigue in 1 patient, grade 3–4 nausea/vomiting in 2 patients, grade 3–4 neurologic toxicity in 1 patient, and no grade 3–4 thrombocytopenia. No toxic deaths were noted. Conclusions: This preliminary data suggests that the combination of Gemcitabine and Irinotecan appears active in metastatic bladder cancer, with manageable toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Oncology Lilly Oncology