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3094 Background: Many preclinical tumor models with mutations in ARID1A and BAP1 are highly sensitive to EZH2 inhibition. Tulmimetostat (CPI-0209) is an investigational oral, next-generation, dual EZH2/EZH1 inhibitor with durable target coverage. Phase I dose escalation established a recommended Phase II dose of 350 mg (Lakhani et al. ASCO 2021). We report preliminary Phase II findings from the ongoing Phase I/II study (NCT04104776). Methods: Phase II is evaluating tulmimetostat 350 mg once daily in 28-day cycles in 6 disease-based cohorts (Table). The Simon 2-stage study design requires 1 response (complete [CR] or partial [PR]) in stage 1 (n = 10 patients [pts]) for expansion to stage 2 (plus n = 19) (except in M4, see table). Primary endpoint is objective response rate (ORR) based on disease-specific criteria; secondary objectives include safety. Results: As of Nov 08, 2022, 62 pts received ≥1 dose (safety evaluable); 48 had ≥1 postbaseline tumor assessment (efficacy evaluable). Pts had median 3.2 years (0.6–19.6) since diagnosis; 77.4% had ≥2 prior lines of therapy. Cohorts M2, M5 and M6 had completed stage 1 enrollment. At cut-off, best responses among evaluable patients (Table) show 4 cohorts have at least 1 confirmed response, including 2 CR and 1 PR in 7 pts with peripheral T-cell lymphoma (PTCL). 47 pts (75.8%) experienced TEAEs leading to dose modifications, 20 (32.3%) had serious TEAEs, and 5 (8.1%) discontinued treatment due to TEAEs. The most frequent TEAEs (≥15% of pts) (any Grade/Grade ≥3) considered at least possibly related to tulmimetostat were thrombocytopenia (51.6%/27.4%), diarrhea (45.2%/12.9%), nausea (37.1%/0%), anemia (30.6%/16.1%), fatigue (29.0%/0%), alopecia (25.8%/1.6%), dysgeusia (24.2%/0%), vomiting (21.0%/0%), and neutropenia (17.7%/14.5%). Conclusions: Based on response criteria of ORR ≥1/10 pts, the ovarian (M2), endometrial (M3), and mesothelioma (M5) cohorts achieved eligibility for stage 2 expansion (not relevant in M4). The safety profile of tulmimetostat is consistent with EZH2 inhibition and previous data. These preliminary findings in heavily pretreated pts with multiple tumor types, including tumors with ARID1A alterations or BAP1 loss, support ongoing investigation of tulmimetostat. Clinical trial information: NCT04104776 . [Table: see text]