Background: In a phase III trial, GD had similar response and survival rates to doxorubicin when administered as first-line therapy to advanced STS pts. G and D have each demonstrated synergy with PD-1 blockade in pre-clinical or clinical studies. We hypothesized that GD plus R would be safe, tolerable, and have synergistic activity in STS. Methods: This is an ongoing open-label, single-center, phase I/II trial of R (INCMGA00012) combined with GD in pts with treatment-naïve unresectable or metastatic high-grade STS. Herein, we report the phase I results, which included a safety run-in followed by a 3+3 dose de-escalation design. G (900 mg/m²) was administered on days 1 and 8 and D (75 mg/m²) on day 8, in 21-day cycles. R (210 mg IV flat dose on the run-in portion and 375 mg on the dose de-escalation portion) was administered on day 1 of each cycle starting in cycle 2 and continued as monotherapy after completion of 6 cycles of GD. The primary endpoint of the phase I was to determine the recommended phase 2 dose (RP2D) of R plus GD. Secondary endpoints included describing the safety, assessing best overall response rate (ORR) by RECIST 1.1, disease control rate (DCR), and progression-free survival (PFS). Results: Thirteen pts were treated, 7on the run-in and 6 on the de-escalation portion. One pt progressed prior to starting R and was replaced. Median pt age was 53 (range 28 – 74) and 7 were female. Histologies included leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (2), pleomorphic liposarcoma (1), angiosarcoma (1), and myxofibrosarcoma (1). The Table lists treatment-related adverse events (TRAEs) that occurred in ≥ 20% pts in descending order of frequency. Additional Grade (Gr) 3 TRAEs occurring in 1 pt each, included: infusion reaction, leukopenia, anorectal infection, neutropenia, and pyelonephritis. Gr 3 pyelonephritis was the only dose-limiting toxicity. There were no Gr ≥ 4 TRAEs. One pt (Gr 3 elevated AST/ALT) required corticosteroids and cessation of study therapy. The RP2D was determined to be 375 mg of R plus GD. Twelve pts were evaluable for response. ORR was 17% (1 of 6; 95% CI 1 - 64%) and 50% (3 of 6; 95% CI 19% - 81%) in the run-in and de-escalation cohorts, respectively. DCR was 100% (6 of 6; 95% CI 52 - 100%) and 83% (5 of 6; 95% CI: 36 - 99%). PFS rates at 24 weeks were 60% (95% CI: 29 - 100%) and 44% (95% CI: 17 - 100%). Conclusions: R plus GD was generally safe and well tolerated with no unexpected safety signals to date. The phase II portion evaluating efficacy of R plus GD at the RP2D is ongoing. Clinical trial information: NCT04577014.

n = pt(s) with TRAE.