Background: Checkpoint inhibitors (CPI) have transformed melanoma treatment but many patients remain refractory. CPI plus i.t. IMO may improve response by activating innate immune function. Based on this we initiated a trial of IMO in combination with ipi or pembrolizumab (pem) in RM. Methods: Adults with RM that progressed during or after ≥ 12 weeks of PD-1 therapy are eligible. IMO, 4 – 32 mg, is given i.t. for 6 doses, along with either ipi or pem. Endpoints are safety, response, biomarkers, and PK. Injected and distant tumors are biopsied pre-treatment and again at 24 hrs (injected tumor), weeks 8 and 13 for immune analyses. Results: As of October 7, 2016, 10 pts have been treated; median age 55 (range: 39-76), 8 with visceral and 1 with brain metastases. Two pts have mucosal histology. 60% have BRAF mutations. Prior duration of anti-PD-(L)1 therapy ranges from 8 to 63 weeks and median time from last PD-1 therapy to onset of study treatment is 6 (4,57) weeks. IMO has been administered at 4, 8, and 16 mg. No DLTs have been observed and there have been no treatment-related discontinuations or deaths. Ipi was discontinued after the second dose in one subject with previous ipi-related hepatitis for recurrent transaminase elevations (grade 4). Grade 3 hypophysitis is the only other immune-related AE (2 pts). Most frequent TEAE (N > 2) are nausea, vomiting, anemia, diarrhea, increases in ALT/AST/GGT/triglycerides, chills, fatigue, pyrexia, and leukopenia; the majority are low-grade. 6 patients are evaluable for response - CR (1), PR (2), SD (2), PD (1) by RECIST1.1. Tumor biopsies show consistent maturation of the myeloid DC1 subset in IMO injected tumors at 24 hrs. Week 8 results are consistent with a higher rate of proliferative (Ki67) effector CD4+ and CD8+ T-cells in responders. Circulating IFNγ shows 2-3 fold increase in responders. Conclusions: The combination of IMO and ipi is tolerable and has activity in PD-1 refractory melanoma. Dose escalation is ongoing and a Phase 2 expansion with both combinations is planned. Updated safety, antitumor activity, PK, and biomarker data will be presented at the meeting. Clinical trial information: NCT02644967