Background: The outcome of high risk stage IIIb and IIIc melanoma patients is poor, with a 5 year overall survival (OS) rate of < 50%. Adjuvant high dose IPI significantly improves 5 year progression free survival (PFS) and OS. In stage IV patients the combination of IPI and NIVO improves response rates (RR) and PFS compared to monotherapy, but at cost of higher toxicity. Neo-adjuvant 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 present. The phase Ib OpACIN study comparing neo-adjuvant and adjuvant IPI and NIVO showed that neo-adjuvant treatment is feasible as all patients underwent surgery on time. The neo-adjuvant pathological RR was 80%, although 18/20 patients (90%) stopped early due to ≥1 grade 3 or 4 immune-related adverse events (irAEs). To date (median follow-up 45 wks), none of the 8 responders in the neo-adjuvant arm have relapsed. This raises the question whether the neo-adjuvant IPI and NIVO schedule can be adjusted to reduce toxicity but preserve efficacy. Methods: The aim of the multi-center phase 2 OpACIN-neo trial is to identify an optimal neo-adjuvant combination scheme of IPI and NIVO. 90 patients with resectable stage III melanoma will be randomized 1:1:1 between three combination schemes of IPI and NIVO. Patients in arm A will receive 2 courses standard regimen IPI 3mg/kg + NIVO 1mg/kg q3wks, in arm B IPI 1mg/kg + NIVO 3mg/kg q3wks, and in arm C 2 courses of IPI 3mg/kg q3wks directly followed (2-24hr) by 2 courses NIVO 3mg/kg q2wks. All patients will undergo surgery at week 6. The primary endpoints are rate of grade 3/4 irAEs, pathological RR, and radiologic RECIST 1.1. An interim analysis is planned after 13 patients have been accrued to each arm (according to the Simon 2-stage design). 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 for translational research. The first center started inclusion in December 2016, until now 2 patients have been enrolled. Clinical trial information: NCT02977052