A phase I study of the EZH2 inhibitor TR115 in patients with relapsed/refractory non-Hodgkin's lymphomas and advanced solid tumors.

7053 Background: EZH2 gain-of-function mutations and overexpression lead to aberrant H3K27me3 levels and result in tumorigenesis and metastasis, including several categories of B cell and T cell lymphoid malignancies, and it is associated with poor clinical prognosis and outcomes. TR115, a novel, highly selective, orally administered EZH2 inhibitor, has demonstrated potent anti-tumor activity in preclinical models. This Phase I study aims to evaluate the safety, tolerability, and preliminary efficacy of TR115 in patients with relapsed/refractory non-Hodgkin's lymphomas (NHL) and advanced solid tumors. Methods: Dose escalation started at 200mg bid and progressed up to 1600mg bid. Patients received TR115 orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or patient withdrawal. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Efficacy was evaluated using Lugano 2014 criteria for lymphomas and RECIST v1.1 for solid tumors. Results: By January 10, 2025, a total of 20 patients were enrolled, including those with angioimmunoblastic T-cell lymphoma (AITL, n=4), diffuse large B-cell lymphoma (DLBCL, n=4), ovarian cancer (n=4), ALK-negative anaplastic large cell lymphoma (ALCL, n-2), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n=2), mycosis fungoides (n=1), follicular lymphoma (FL, n=1), extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (MALT, n=1) and breast cancer (n=1). Median age was 61 (range 37-77) with 10 (50%) males. Most were heavily pretreated with a median of 2 previous lines of therapy. the most common TRAEs (all grades/Grade ≥3) included thrombocytopenia (50%/15%), leukopenia (45%/10%)，anemia (40%/15%), neutropenia (35%/10%), hypertriglyceridemia (35%/5%), elevated blood creatinine (35%/0%), elevated lactate dehydrogenase (25%/0%), hypokalemia (25%/5%), hyperbilirubinemia (20%/0%), adynamia (20%/5%), Hypoproteinemia (20%/0%), and upper respiratory tract infection (10%/5%). Of the 11 patients with non-Hodgkin's lymphomas evaluable for response, the overall response rate (ORR) was 63.6%, and the disease control rate (DCR) was 81.8%. 6 patients with PTCL had an ORR of 100%, and 4 continue to receive treatment with the investigational drug. One PTCL-NOS patient achieved a complete response (CR) remaining on treatment at Cycle 16. PK parameters AUC 0-24h and C max were dose proportional with median T max 2 hours. Conclusions: In this study, TR115 exhibited a favorable safety profile and promising efficacy in patients with relapsed/refractory non-Hodgkin's lymphoma, especially in relapsed/refractory PTCL patients. Further investigation of TR115 alone or in key therapeutic combinations is warranted. (NCT05650580). Clinical trial information: NCT05650580 .