Background: Ipilimumab has significantly improved overall survival of patients with metastatic melanoma. However in unselected patients only about 10-15% of all patients treated with ipilimumab show objective response. Disease control rate ranges about 30%. The NY-ESO-1 antigen belongs to the group of cancer/testis antigens. It is expressed in about 30% of metastatic melanoma. Spontaneous antibody formation can be observed in about 20% of patients with metastatic melanoma. Several preclinical and clinical data provide strong evidence for the immunogenicity of NY-ESO-1. Nevertheless, the role of humoral immune responses potentially reflecting tumor immunity is unclear. Data regarding the correlation between the presence of spontaneous antibodies against NY-ESO-1 and response to ipilimumab are conflicting. Methods: CTLA-4 NY-ESO-1 is a single arm phase II trial to determine the efficacy, safety and tolerability of ipilimumab in patients with melanoma stage III and IV and spontaneous preexisting humoral immune response against NY-ESO-1. 25 patients with detectable antibodies against NY-ESO-1 (detected by ELISA) receive ipilimumab at a dosage of 10 mg/kg during an induction period (week 1, 4, 7, 10), followed by a maintenance period with application every 12 weeks until week 48, tumor progression or severe toxicity. Primary endpoint is Disease Control Rate (DCR) at week 12, secondary endpoints include overall survival and progression-free survival. The main analysis includes a hypothesis test concerning DCR following the A’Hern’s single-stage design. Results: This is an unplanned interim analysis requested by DSMB: 23 of 25 patients have been enrolled. Response evaluation according to immune-related response criteria is available for 22 patients: irPR in 5 patients (22.7%), irSD in 6 patients (27.3%), irPD in 7 patients (31.8%), 4 patients (18.2%) stopped study treatment prematurely due to immune-related AEs. Treatment related grade 3-4 toxicity was observed in 8 patients. Conclusions: Preliminary data suggest that ipilimumab shows encouraging activity in patients with metastatic melanoma and preexisting antibody responses against NY-ESO-1. Clinical trial information: 01216696.