Background: Sarcoma cells are most immunogenic at the onset of cancer. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To evaluate the safety of ipilimumab (I), a CTLA4 inhibitor, nivolumab (N), a PD-1 inhibitor, and escalating doses of trabectedin (T), a marine-derived natural alkaloid, in advanced soft tissue sarcomas (STS), (2) To investigate the BORR, DCR, PFS and OS, and (3) to correlate response with immune cell trafficking in the tumor microenvironment. Methods: This is an IRB-approved dose-seeking phase 1/2 study using defined doses of I (1 mg/kg IV q 12 weeks), N (3 mg/kg IV q 2 weeks) and escalating doses of T (1.0, 1.3, 1.5 mg/m² IV q 3 weeks), employing “cohort of three” design, with a Phase 2 component using the MTD of T. Results: Phase 1 safety analysis: At Dose 1: Grade 3 treatment related adverse events (TRAEs): fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs: thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs: anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). At Phase 2, Grade 4 TRAEs: increased CK (n = 1); Grade 3 TRAEs: increased ALT (n = 4), anemia (n = 3) neutropenia (n = 1), portal cellulitis (n = 1). Efficacy analysis: Phase 1 (n = 9): At Dose 1: DCR 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1, rhabdomyosarcoma), DCR 60%, median PFS, > 42 weeks; median OS, > 47 weeks. Phase 2 (n = 16): PR (n = 3; 1 liposarcoma, 1 leiomyosarcoma, 1UPS); BORR 18.75%, DCR 87.5%, median PFS, > 19 weeks; median OS, > 26 weeks. Surgical resection was undertaken in 1 patient with SD after 4 cycles. The surgical specimen showed 80% necrosis and greater number (30%) of CD8+ killer T cells, 10% PD-L1+ cells in the TME compared to that of archived pre-treatment tumor. Conclusions: Taken together, these data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. The phase 2 part of the study is on-going. Clinical trial information: NCT03138161