Background: PD-L1 is expressed in soft tissue sarcomas (STS) but PD-1 inhibition alone has limited activity. This primary resistance may partly be explained by IDO pathway activation. Epigenetics modifications have also been recognized as mechanisms of resistance to PD-1 inhibition. We hypothesized that the association of MK3475 (PZ) + mCP, either alone or with IDO inhibitor Epacadostat (EP), TLR4 agonist G100 or EZH2 inhibitor Tazemetostat (TZ) could have a synergistic activity with good safety in pts with advanced STS, with a focus on Undifferentiated Pleomorphic Sarcoma (UPS). Methods: This is a multicenter, prospective open-labeled single-arm phase II trial with ten independent strata assessing: PZ 200 mg IV on day 8 of a 3 weeks cycle, mCP 50 mg b.i.d. orally one week on /one week off: - in leiomyosarcoma (stratum 1), UPS (stratum 2), other STS (stratum 3), osteosarcoma (stratum 4) and GIST (stratum 5) - + EP orally 100 mg b.i.d. in UPS (stratum 6) and other STS (stratum 7) - + G100 intratumor at 20 µg once weekly for 6 weeks in STS (stratum 8) - + TZ orally 800 mg b.i.d. in UPS (stratum 9) and other STS (stratum 10) Main eligibility criteria are - adult pts with metastatic or unresectable locally advanced, histologically confirmed sarcoma by central review, - measurable progressive disease (RECIST v1.1) – no more than 2 previous lines of systemic treatment – PDL1 and/or IDO expression on immune cells > 1% on < 3 months old tumor sample (strata 6 and 7) Primary endpoint is 6-month non progression as per RECIST v1.1. Secondary endpoints encompass toxicity according to NC-CTCAE v4.03, best overall response RECIST v1.1, 1-year progression-free survival and overall survival, growth modulationi, pharmacodynamics on mandatory collection of blood and tumor samples at baseline and on treatment. Each strategy will follow a 2-stage Simon’s design. PZ+mCP + either EP, G100 or TZ will be considered promising if at least 8 non-progressions at 6 months are observed among 29 evaluable pts. In this regards, 32 pts will be recruited in each stratum. Strata 1-3, 5 have been reported. Stratum 4 is on hold for intermediate analysis. Opening of strata 6-10 is awaited by June 2018. Clinical trial information: NCT02406781