Phase II dose optimization with EZH2/EZH1 inhibitor tulmimetostat in patients (pts) with advanced solid tumors or hematologic malignancies.

3097 Background: Phase I dose-finding recommended a Phase II dose of 350 mg for the investigational oral, next-generation, dual EZH2/EZH1 inhibitor tulmimetostat (1), with preliminary Phase II results previously reported (2). To find an optimal dose, design of the ongoing Phase II part was later updated under the FDA’s dose-optimization paradigm (NCT04104776). Here we report updated preliminary findings including dose expansions. Methods: Phase II is evaluating tulmimetostat ≤350 mg once daily (QD) in 28-day cycles in 6 disease-based cohorts. The dose-optimization design randomizes further pts with ovarian clear cell carcinoma (OCCC; M2)/endometrial carcinoma (EC; M3) to 200/300 mg tulmimetostat QD. Primary endpoint is objective response rate (complete response [CR]/partial response [PR]); secondary objectives include pharmacokinetics/pharmacodynamics and safety. Results: As of Oct 15, 2023, 117 pts received ≥1 dose (safety set); 111 had ≥1 post-baseline tumor assessment or discontinued prior to it (efficacy set). Median time since diagnosis was 2.8 years (0–19.6); 86.3% of pts had ≥2 prior lines of therapy. At cut-off, best responses of ≥1 CR/PR were seen in 5 cohorts (Table). 74.4% had dose modifications due to treatment-emergent adverse events (TEAEs), 41.9% had ≥1 serious TEAE, and 9.4% discontinued therapy due to TEAEs. Most frequent TEAEs (≥35% of pts; any grade/Grade ≥3) considered possibly related to treatment were diarrhea (49.6%/10.3%), thrombocytopenia (48.7%/24.8%), anemia (39.3%/16.2%), and nausea (35.9%/2.6%). Phase I/II data showed a direct correlation between increasing doses (50–375 mg) or exposure (area under the curve 0–24 hours or maximum concentration) and larger changes in gene expression, which plateau at higher doses (≥225–≤375 mg). Conclusions: The evolving Phase II data, including early data from lower doses, continue to show signs of antitumor activity/disease stabilization. The safety profile is consistent with EZH2 inhibition. These preliminary findings in heavily pretreated pts with multiple tumor types and evolving dose-optimization data support ongoing investigation of tulmimetostat. 1. Lakhani et al. ASCO 2021. 2. Drescher et al. ASCO 2023. Clinical trial information: NCT04104776 . [Table: see text]