Background: Neoadjuvant ipilimumab (ipi) at 3 or 10 mg/kg in combination with high dose IFNα2b (HDI) for locally/regionally advanced or recurrent melanoma may improve the clinical outcomes of these high risk patients (pts), and provide access to blood and tumor pre/post ipi-HDI to illuminate the host effector and suppressor immune mechanisms. Methods: Pts were randomized to ipi 3 or 10 mg/kg IV every 3 weeks (wk) x 4 doses bracketing definitive surgery, then every 12 wks x 4. HDI (20 MU/m²/d IV x 5 days (d)/wk for 4 wks then 10 MU/m²/d SC every other d TIW for 48 wks) was given concurrently. Tumor samples were obtained at baseline and at definitive surgery (wk 6-8) and serum/PBMC at baseline, 6 wks, 3, 6, 12 months (mo). Results: Twenty seven pts (17 male, 10 female, 20 cutaneous primary, 7 unknown), age 37-76 were treated (14 at ipi 3 mg/kg, 13 at 10 mg/kg). Three had Stage IIIB (N1b, N2b, N2c), 23 IIIC (N3) and 1 IV (not evaluable) melanoma. Over 120 cycles have been delivered to date (median 4). Worst toxicities included grade (Gr) 3 (in ≥ 2pts): diarrhea/colitis (4 pts; 15%), ↑AST/ALT (5; 19%), rash (7; 26%), hypophysitis (2, 7%), adrenal insufficiency (2, 7%), ↑lipase (3; 11%), pruritus (2, 7%), fatigue (15, 56%), anorexia (4, 15%), hypophosphatemia (4, 15%), neutropenia (2, 7%), lymphopenia (2, 7%), ↑creatinine (2, 7%), hyperuricemia (2, 7%). There were 2 Gr 4 events (AST, hyponatremia). More Gr 3/4 adrenal insufficiency, hypophysitis, ↑lipase and ↑AST/ALT were seen at ipi 10 versus ipi 3 mg/kg. All AEs were manageable. Among 26 evaluable pts, 7 relapsed and 2 died. Median follow-up for 19 pts who have not relapsed is 13.2 mos (range 1.3 - 30). The radiologic preoperative response rate (WHO; unconfirmed) was 35% (95% CI = 17-56); 4 pts at ipi 3 and 5 at ipi 10. The pathologic complete response rate (no viable tumor on histologic assessment) was also 35% (95% CI = 17-56); 5 pts at ipi 3 and 4 at ipi 10. Conclusions: Neoadjuvant ipi-HDI exhibits promising clinical activity at both dose levels of ipi, but appears more toxic at ipi 10 mg/kg. Studies of predictive biomarkers and mechanisms are ongoing. Longer follow up is underway in order to define the long term benefits and the optimal ipi dosage for future testing. Clinical trial information: NCT01608594