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

Background: HZ-H08905 is a first-class and potent CK1ε/PI3Kδ dual inhibitor with nano-molar inhibitory potency at both enzyme and cellular levels. Dual inhibition of CK1ε and PI3Kδ may exert synergistic effects through inhibiting both CK1ε/Wnt signaling and PI3K signaling in malignant lymphocytes, and enhance anti-tumor immunity through regulation of tumor microenvironment. 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 non-Hodgkin lymphoma (NHL) subtypes, including CLL, DLBCL, FL, MCL, WM, PTCL and NKTL.

Aims: To describe the updated results from patients with B-cell lymphomas (BCM) enrolled in the phase 1 portion of the open-label, first-in-human trial in China, HZ-H08905-101 (CTR20213233).

Methods: The primary objectives of this phase I study were to assess safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of HZ-H08905 monotherapy and secondary objectives were to evaluate pharmacokinetic properties and preliminary anti-tumor activity of HZ-H08905. Eligible patients must have a histologically confirmed diagnosis of B-cell lymphomas, whose disease had relapsed after, or was refractory to or intolerant to the last therapy, an ECOG performance status of 0-2, and adequate organ function. For patients with indolent NHL subtypes, such as CLL/SLL, FL and WM/LPL, at least two previous treatment regimen were required; for MCL and other indolent NHL, patients must have received ≥ 1 prior systematic regimen; for DLBCL and other aggressive, patients must have received ≥ 1 prior systematic regimen and meet the following criteria: have not achieve CR after second-line therapy, or have progression of disease during any treatment, or recurrence within 12 months after autologous stem cell transplantation, or recurrence after remission (if patients had received first-line treatment, relapse should within half a year). 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 (50mg once daily), followed by a 3 + 3 design (100, 200, 300 or 450 mg once daily). Dose-limiting toxicity (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 IWWM-7 for WM, or IWCLL 2018 for CLL/SLL, or Lugano 2014 criteria for other NHL.

Results: As the data cutoff of 28 Jun 2024, 24 patients with BCM were enrolled and treated with HZ-H08905 including FL (12 patients), DLBCL (5 patients), MCL (3 patients), WM (2 patients), CLL (1 patient) and MZL (1 patient). 1 patient received 50mg/day, 4 patients received 100mg/day, 16 patients received 200mg/day and 3 patients received 300mg/day. The median age was 58 years (range, 43-70 years), with a median ECOG of 1 (range, 0-2), and a median of 3 prior systemic therapies (range, 1-5). No DLT occurred at all any dose level and MTD was not reached. 21 of 24 pts with BCM (87.5%) experienced a treatment related adverse event (TRAE). TRAEs occurring in ≥10% of patients were neutropenia, leukopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated serum creatinine, thrombocytopenia, elevated blood bilirubin, rash, hypercholesteremia, pneumonia, upper respiratory infection, hyperlipidemia, hypertriglyceridemia, hyperuricemia, anemia, elevated blood lactate dehydrogenase and elevated gamma glutamyl transpeptidase. TRAEs of ≥Grade 3 (≥5%) were neutropenia, leukopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase, pneumonia and thrombocytopenia. The median time to response (mTTR) was 1.87 months (95%CI: 1.87, 1.93). With a median follow-up of 8.3 months, the overall response rate (ORR) was 70.8% (17/24), and complete response rate (CRR) was 33.3% (8/24). Among the 12 patients with FL, the ORR was 83.3% (10/12) and CRR was 50.0% (6/12).

Conclusions: These results demonstrated that HZ-H08905 monotherapy was well tolerated and showed significant efficacy in patients with R/R BCM, particularly R/R FL.