Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. Over 90% of tumors have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. Tazemetostat (an EZH2 inhibitor) has been approved by FDA for clinical use in ES. HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat in INI1-loss preclinical models. Methods: This is a first-in-human, open-label, multi-center, Phase (Ph) I/II study in patients (pts) with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors. Ph I is composed of two parts: dose escalation and dose extension part. Local pathologically documented, advanced recurrent or metastatic ES pts who received prior systemic anti-tumor therapies or have no standard therapy are eligible. HH2853 was administered orally twice daily (BID) on a continuous 28-day treatment cycle. Safety and clinical activity of HH2853 were assessed in pts with ES from the Ph I part. Results: Between Dec 2, 2021 and Nov 7, 2022, 32 pts with pre-treated ES were enrolled to three dose levels (400, 600, and 800 mg BID) from 4 sites in China. Median prior lines of therapy was two. 12 (37.5%) pts received ≥3 lines of prior therapies. 30 (93.8%) pts had documented loss of INI1 expression by local immunohistochemical analysis. There were 18 (56.3%) pts with proximal subtype. As of Jan 4, 2023, at a median treatment duration of 124 days, the most common treatment-related adverse events (TRAE) were diarrhea (59.4%), blood bilirubin increased (43.8%), white blood cell count (WBC) decreased (34.4%), rash (31.3%), anemia (25.0%), hypokalemia (21.9%), and platelet count (PLT) decreased (21.9%). TRAEs of ≥Grade 3 included diarrhea, WBC decreased, anemia, hypokalemia, and neutrophil count decreased (6.2%, each), and blood bilirubin increased, PLT decreased, blood creatine phosphokinase increased, and hyperglycemia (3.1%, each). TRAEs leading to dose interruption or reduction were reported in 21.9% and 12.5% pts, respectively. No TRAE led to dose discontinuation or death. Tumor responses were observed from 400 to 800 mg BID. Overall response rate (ORR) was 15.6% (5/32) per investigator assessment according to RECIST 1.1. Three pts had unconfirmed response waiting to be confirmed at the next scheduled assessment, expecting to bring the total ORR to 25% [95% CI 11.5 – 43.4]. Median time to response was 1.9 months. One patient with complete response (CR) has responded for 222 days from the initial response. Disease control rate (DCR) (DCR = CR + partial response + stable disease at 6 weeks) was 78.1% [95% CI 60-90.7]. Conclusions: HH2853 showed an acceptable safety profile and promising anti-tumor activity in heavily pretreated ES pts with a wide therapeutic window, providing evidence for further investigation. Clinical trial information: NCT04390737.