Purpose: Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade ≥2 diarrhea in ipilimumab-treated patients with advanced melanoma. Experimental Design: Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits. Results: Budesonide did not affect the rate of grade ≥2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed. Conclusions: Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy. (Clin Cancer Res 2009;15 (17):5591-8) Localized melanoma can be effectively treated by surgery (1), but new therapies for unresectable disease are urgently needed. Dacarbazine is the commonly used standard treatment for advanced melanoma (2, 3), but no systemic treatment has shown improved survival compared with dacarbazine in randomized clinical trials (4-7). Recent immunotherapy trials have shown median overall survival (OS) time of 11.4 months with highdose interleukin 2 (8) and 11.7 months for tremelimumab (9). A recent meta-analysis of 42 phase II trials done by the cooperative groups between 1975 and 2005 in patients with metastatic melanoma documented a median survival time of 6.2 months, with a 25.5% 1-year survival rate (10).Ipilimumab (Bristol-Myers Squibb and Medarex) is a fully human monoclonal antibody directed against CTL antigen-4 . CTLA-4 is a key negative regulator of the T-cell immune response, and preclinical animal studies have shown that blocking CTLA-4 enhances adaptive immune responses and induces tumor regression (16,17). In clinical trials,

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