Background: The outcome of high risk stage III melanoma patients (pts) is poor, with a 5 year overall survival (OS) rate of < 50%. Adjuvant (adj) high dose IPI significantly improves 5 year progression free survival (PFS) and OS and adj NIVO improves the median PFS even more. In stage IV pts, the combination of IPI and NIVO improves response rates (RR) and PFS compared to monotherapy, but at cost of higher toxicity. Neo-adjuvant (neoadj) treatment may be a favorable approach as immune checkpoint inhibition (ICI) is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen. The phase Ib OpACIN study compared neoadj versus adj IPI plus NIVO. The pathological RR (pRR) was 80% in the neoadj arm, and to date after a median follow-up of 24 months, none of the responders has relapsed, while 4/10 pts have relapsed in the adj arm. Moreover, pts in the neoadj arm expanded more tumor-resident TCR clones than adj treated pts. Neoadj IPI+NIVO was feasible, but toxicity was high with 90% grade 3/4 immuun-related adverse events (irAE) in both arms. This raises the question whether neoadj IPI plus NIVO can be alternatively scheduled to reduce toxicity but preserve efficacy. Methods: The aim of the multi-center phase 2 OpACIN-neo trial is to identify an optimal neoadj combination scheme of IPI and NIVO. 90 pts with resectable stage III melanoma will be randomized 1:1:1 between three different combination schemes of IPI and NIVO (Arm A: 2x IPI 3mg/kg plus NIVO 1mg/kg q3wks, Arm B: 2x IPI 1mg/kg plus NIVO 3mg/kg q3wks, Arm C: 2x IPI 3mg/kg q3wks directly followed by 2x NIVO 3mg/kg q2wks). All pts will undergo surgery at week 6. Primary endpoints are rate of grade 3 and 4 irAEs, pRR, and radiologic RR according to RECIST 1.1. Major inclusion criteria are: ≥1 measurable lymph node metastases (according to RECIST 1.1) that can be biopsied, no history of in-transit metastases in the last 6 months, and naïve for ICI. Baseline biopsies and blood samples (week 0, 6, 12) will be taken. An interim analysis was planned after 13 pts had been accrued to each arm (according to the Simon stage-2 design). Pre-specified activity goals for the first stage of accrual were met; until now 56 of 90 pts have been enrolled. Clinical trial information: NCT02977052