Dual CK1ε/PI3Kδ Inhibitor HZ-H08905, Exhibits As a Potential Therapeutic Strategy for Hematologic Malignancies

HZ-H08905 is a first-class and potent CK1ε/PI3Kδ dual inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. In vivo tumor growth inhibition is also observed in multiple B-cell lymphoma xenograft mouse model including OCI-LY10 and SU-DHL-6. HZ-H08905 has unique structure and activity profile distinct from other PI3Kδ inhibitors in development: 1) dual inhibition of CK1ε and PI3Kδ may exert synergistic effects through inhibiting both CK1ε/Wnt signaling and PI3K signaling in malignant lymphocytes, 2) dual inhibition of CK1ε and PI3Kδ also enhance anti-tumor immunity through regulation of tumor microenvironment; 3) preclinical studies also suggested an improved therapeutic window with a differentiated safety profile.

HZ-H08905-101 is an ongoing Phase 1, first-in-human, open-label, multicenter, multiple-dose ascending and expansion study of oral HZ-H08905 monotherapy in patients with relapsed/ refractory advanced hematologic malignancies in China (CTR20213233). The aim of this study was to investigate the safety, tolerability, and pharmacokinetic properties of HZ-H08905, in order to determine the maximum tolerated dose (MTD) based on dose limiting toxicity (DLT) and assess preliminary anti-tumor activity in patients with non-Hodgkin lymphoma (NHL), including B-cell lymphoma and T-cell lymphoma. The phase Ia (dose escalation) part of the study was designed to determine MTD and recommended dose for expansion (RDE) of HZ-H08905. HZ-H08905 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Efficacy evaluable patients included all dosed patients who underwent their first response evaluation or discontinued therapy. Response was assessed at the beginning of cycle 3 and then every 12 weeks from cycle 3 and every 24 weeks from cycle 18, and was measured according to IWWM-7 for WM, or IWCLL 2018 for CLL/SLL, or Lugano 2014 criteria for other NHL. Safety was assessed in all patients.

The preliminary results showed that HZ-H08905 was well tolerated and showed clinical activity in patients with R/R NHL, especially R/R PTCL. The efficacy, safety, and tolerability of HZ-H08905 in R/R PTCL patients at recommended phase II dose (RP2D) established in the phase I dose escalation and expansion part will be investigated in phase 2.

No relevant conflicts of interest to declare.