A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial of HH2853 in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphoma

Introduction Peripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, whereas treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. HH2853, the novel, potent and selective dual inhibitor of Enhancer of Zeste Homolog 1 and 2 (EZH1/2), has demonstrated a clinical benefit with a favorable safety profile in Phase 1 and Phase 2 trials in solid tumors and R/R non-Hodgkin's lymphoma (NHL) previously. Here we report the efficacy and safety data from phase 1b trial of HH2853 in r/r PTCL.

Methods The Phase 1b clinical trial in PTCL (CTR20221416) was conducted from July, 2022 to June 15, 2023 at 15 sites in China. This study consisted of two parts. In part 1, 3+3 dose-escalation design with three dose levels of HH2853 (300mg, 400mg, 600mg BID) was used to identify the MTD and recommended Phase II dosage (RP2D) of HH2853. Part 2 was dose expansion at two dose groups (300mg and 400mg BID). HH2853 was orally dosed until disease progression, intolerable toxicity or withdrawal from the study. Safety was evaluated according to CTCAE v5.0. Tumor assessments were performed according to LUGANO 2014 every 2 treatment cycles (28-day/cycle). A final data cut off (DCO) on June 15, 2023 was conducted for safety and efficacy assessments. To that date, there were still 25 pts (73.5%) remained on HH2853 treatment.

Results In this study in r/r PTCL, 34 pts enrolled with different PTCL histology types, including AITL (14 pts, 41.2%), PTCL-NOS (11 pts, 32.4%), ALK ^-ALCL (4 pts,11.8%), NKT (2 pts, 5.9%), TFH (2 pts, 5.9%), SKIN-PTCL (1 pt, 2.9%). Pts were a median age of 58 years (range: 34 to 79), ECOG 0-1 (ECOG 0, 9 pts, 26.5%, ECOG 1, 25 pts, 73.5%), had a median of 2 lines (range 1 to 5) prior systemic therapies, 6 pts (17.6%) had bone marrow involvement at the baseline. With 30 pts (88.2%) having prior CHOP or CHOP-like therapy，with 14 pts (41.2%) were refractory to their last treatment. 1pts (2.9%) had undergone hematopoietic stem cell transplantation.

32 patients (92.1%) had experienced a treatment related adverse event (TRAE), 7 pts (20.6%) experienced grade ≥3 TRAE. The most common TRAEs (≥10%) were PLT decreased (14 pts, 41.2%) , anaemia (13 pts, 38.2%)，and diarrhoea (11 pts, 32.4%). The frequently reported TRAEs of grade ≥3 with an incidence of ≥10% were PLT decreased (5 pts, 14.7%) and neutrophil count decreased (4 pts, 11.8%). 8 pts (23.5%) had dose interrupted due to TRAE. 3 pts (8.8%) had dose reductions due to TRAE from 600 to 400 mg BID, 1 pts (6.3%) had dose reductions from 400 to 200 mg BID, and 1 pts (2.9%) discontinued from the study due to TRAEs. The safety profile was consistent to that had been observed in HH2853 studies. 1 pt (2.9%) at 600mg BID experienced dose limiting toxicity (DLT)due to grade 4 PLT decreased. The majority of TRAEs were reversible or clinically manageable.

Among the 34 enrolled pts, 28 patients had the evaluated response, the Overall Response Rate (ORR) was 60.7% (17 pts), including 21.4% (6 pts) Complete Responses (CR), 39.3% (11 pts) Partial Responses (PR) and 14.3% (4 pts) Stable Disease (SD), contributing to an 75.0% (21 pts) Disease Control Rate (DCR). The median time to response (mTTR) was 1.87 months (95% CI: 1.77, 2.17). At DCO the median follow up of the pts in the study was 2.79 month (IQR: 1.94, 5.88). The median Duration of Response (mDOR), the median Progression Free Survival (mPFS) and the median OS (mOS) had not reached. The 3-month PFS rate was 74.44% (95%CI:53.62%,86.95%). The 6-month OS rates was 91.97% (95%CI: 71.50%, 97.93%).

Conclusions The selective EZH1/2 dual inhibitor HH2853 demonstrated good safety and promising efficacy in r/r PTCL patients, indicating its potential as a therapeutic option for this difficult to treat patient population.