Abstract
BACKGROUND: Peripheral T-cell lymphoma (PTCL) is an aggressive malignancy with limited treatment options and poor prognosis, particularly for relapsed or refractory (r/r) patients. HH2853, a novel dual inhibitor of EZH1/2, has previously demonstrated clinical benefits in solid tumors. Here, we report safety and efficacy data from a phase Ib trial of HH2853 in r/r PTCL. METHODS: A phase Ib clinical trial in PTCL was conducted from July 2022-August 2023 at 15 sites in China. The study employed a dose-escalation phase (300 mg, 400 mg, and 600 mg BID) to determine the recommended phase II dosage (RP2D), followed by a dose expansion phase (300 mg and 400 mg BID). The primary endpoints were safety and the overall response rate (ORR). RESULTS: Thirty-four patients with various r/r PTCL histology types, a median age of 58 years, and a median of 2 prior systemic therapies were enrolled. Treatment-related adverse events (TRAEs) were observed in 92.1% of the patients, with 20.6% experiencing grade 3 TRAEs. The most common TRAEs included anemia (67.6%), thrombocytopenia (52.9%), leukopenia (44.1%), and diarrhea (38.2%). One patient (2.9%) receiving 600 mg BID experienced dose-limiting toxicity due to grade 4 thrombocytopenia. The dose of 400 mg BID was selected as the RP2D. The ORR was 67.6%, comprising 29.4% complete remission and 38.2% partial remission. As of the data cutoff in September 2024, the median follow-up period was 15.7 months, with a median duration of response of 14.8 months; overall survival had not yet been reached. CONCLUSIONS: The selective EZH1/2 dual inhibitor HH2853 demonstrated acceptable and manageable safety profiles and promising efficacy in r/r PTCL patients, indicating its therapeutic potential for this difficult-to-treat patient population. TRIAL REGISTRATION: NCT04390737.