Preliminary Efficacy and Safety of the CK1ε/PI3Kδ Dual Inhibitor HZ-H08905 in Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphomas: Results from the Phase 1 HZ-H08905-101 Study

Background: Fibroblastic reticular cells (FRCs) play a crucial role in providing structural support within lymphoid tissues and contribute significantly to the unregulated proliferative behavior of T lymphoma cells through the secretion of multiple chemokines. Interfering with the production of these chemokines offers a promising approach to disrupt the crosstalk between FRCs and T lymphoma cells, potentially inhibiting T lymphoma cell proliferation. Such targeted interference could yield beneficial clinical outcomes by curbing the unchecked growth of T lymphoma cells in clinical settings. HZ-H08905 is a first-class and potent CK1ε/PI3Kδ dual inhibitor with nano-molar inhibitory potency at both enzyme and cellular levels. We have demonstrated that the concurrent inhibition of CK1ε and PI3Kδ disrupts the crosstalk between FRCs and T lymphoma cells, thus eliciting a robust antitumor activity in T lymphoma cells in vitro and in vivo. The phase I study of HZ-H08905 was previously reported (Abstract 4428, ASH2023), demonstrating that HZ-H08905 monotherapy was well tolerated and showed promising efficacy in patients with several NHL subtypes, including CLL, DLBCL, FL, MCL, WM, PTCL and NKTL. Aims: To describe the updated results from the phase I portion of the open-label, first-in-human trial HZ-H08905-101 (CTR20213233) in China in patients with PTCL. Methods: The primary objectives of this phase I study were to assess safety/tolerability, MTD, and clinically recommended dose of HZ-H08905 monotherapy. The secondary objectives were to evaluate pharmacokinetic properties and preliminary anti-tumor activity of HZ-H08905. Eligible patients must have a histologically confirmed diagnosis of PTCL, whose disease had relapsed after, or was refractory to or intolerant to, at least one previous treatment regimen (≥1 prior therapies), an ECOG performance status of 0-2, and adequate organ function. HZ-H08905 was administered as oral tablets once daily continuously in 28-day cycles until disease progression or unacceptable toxicity. The dose escalation part was initiated with a dose titration in the initial cohort (50 mg once daily), followed by a 3 + 3 design (100, 200, 300 or 450 mg once daily). DLT for each cohort was evaluated in the first 28-day cycle. Dose expansion was conducted in selected doses and cohorts. Safety was assessed per CTCAE 5.0 and efficacy was measured according to Lugano 2014 criteria. Results: As the data cutoff date of 28 Jun 2024, 50 patients with relapsed and/or refractory PTCL were enrolled and treated with HZ-H08905, including AITL (25 patients), PTCL-NOS (20 patients), 4 ALK-negative ALCL (4 patients) and EATCL (1 patients). 4 patients received 100mg/day, 31 patients received 200mg/day, 12 patients received 300mg/day and 3 patients received 450mg/day. The median age was 62 years (range, 38-78 years), with a median ECOG performance status of 1(range:0-1), and a median of 2 prior systemic therapies (range, 1-5). No DLT were observed at any dose level and MTD was not reached. TRAEs occurring in ≥10% of patients were neutropenia, leukopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase, thrombocytopenia, pneumonia, anemia, rash, elevated serum creatinine, sinus bradycardia, hyperuricemia, abnormal liver function, hypertriglyceridemia, diarrhea, and dermatitis medicamentosa. TRAEs of ≥Grade 3 (≥5%) were neutropenia, pneumonia, leukopenia, thrombocytopenia, elevated aspartate aminotransferase, anemia and dermtitis medicmentose. With a median follow-up of 13.0 months, the ORR was 64.0% (32/50), with 30.0% (15/50) achieving CR. The median time to response (mTTR) was 1.91 months (95%CI: 1.87, 2.10). At the clinically recommended dose of 200mg/day, for AITL and PTCL-NOS patients, the ORR was 68.8% (11/16) and 66.7% (8/12), CRR was 31.3% (5/16) and 33.3% (4/12), respectively. For patients with AITL and PTCL-NOS not previously treated with HDAC inhibitors, the CRR was 60.0% (3/5) and 80.0% (4/5), respectively. Conclusions: The dual inhibition CK1ε and PI3Kδ by HZ-H08905 represents a novel mechanism for disrupting the crosstalk between FRCs and T lymphoma cells. Monotherapy of HZ-H08905 was well tolerated and demonstrated significant efficacy in patients with R/R PTCL in phase I study. Currently, a randomized, double-blind, active-controlled phase 3 study is ongoing in China to evaluate HZ-H08905 in patients with R/R PTCL as a pivotal study.