TPS9615 Background: Adjuvant anti-PD1 (nivolumab or pembrolizumab) has been shown to improve relapse free survival for patients with high-risk stage II melanoma (IIB-C). However, this therapy probably won’t be reimbursed as standard of care in most European countries due to high costs, and the benefit-risk-ratio. For macroscopic stage III melanoma, neoadjuvant ipilimumab (IPI; anti-CTLA4) plus nivolumab (NIVO; anti-PD1) has been shown to induce high pathologic response rates in the resected lymph nodes, long-term event free survival, and this schedule is currently being compared to adjuvant NIVO in a phase 3 study (NCT04949113). This combination schedule, however, is unsuitable for earlier disease stages, due to high costs and clinical toxicity. In preclinical models, a local tumor draining lymph node directed delivery of anti-PD-1 plus anti-CTLA-4 has been demonstrated to outperform systemic administration on induction of T-cell proliferation and tumor control. In patients, local delivery of anti-PD-1 or anti-CTLA-4 has been suggested to be equally effective in tumor control with a reduction of adverse events. These data have formed the rationale for testing intradermal injections at the excision site of the primary tumor with IPI and NIVO prior to the re-excision and sentinel node procedure in high-risk stage II melanoma patients. Methods: This multicenter, dose-escalating phase Ib/II trial, using a Simon’s two-stage design, is the first trial to test feasibility and efficacy of intradermal IPI plus NIVO in high-risk stage II melanoma patients. In total 21 to 80 patients, diagnosed with a stage T3-4 cutaneous melanoma with ≥ 50% chance of positive sentinel node, naïve for re-excision, sentinel node surgery and immunotherapy, will be included in this trial. Patients will receive 2 cycles of intradermal IPI 0.5 mg + NIVO 1 mg at the excision site of the primary melanoma (every 3 weeks; arm A); 6 cycles intradermal IPI 0.5 mg + NIVO 1 mg (every week; arm B); 2 cycles intradermal IPI 10 mg + NIVO 20 mg (every 3 weeks, arm C); or 2 cycles of intravenous nivolumab 240 mg every 3 weeks combined with the most optimal intradermal regimen of IPI + NIVO (based on the results of arm A, B or C) in arm D. In week 6, patients will undergo sentinel node surgery, whereafter only patients with a non-MPR (>10% vital tumor) will be treated with adjuvant anti-PD1 according to current standard of care. We expect the first patient to be enrolled in March 2024and to be accruing for 1-1.5 years. Clinical trial information: NCT06240143 .