Covalent Bruton's tyrosine kinase inhibitor HZ-A-018 in patients with relapsed or refractory B cell malignancies: A...

HZ-A-018 represents a highly selective, covalent, novel inhibitor targeting Bruton's tyrosine kinase (BTK). This multicenter, open-label phase I study enrolled 32 patients with relapsed/refractory B cell malignancies (including diffuse large B cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma) in dose-escalation and -expansion phases. Thirty-one patients received treatment: 15 in the dose-escalation phase (75-550 mg once daily) and 16 in the expansion phase (300 mg once daily). No dose-limiting toxicities or maximum tolerated dose were identified. The most common treatment-emergent adverse events included cytopenias, rash, and hypertension. Among 29 efficacy-evaluable patients, with a median follow-up of 4.9 months, the overall response rate was 44.8%. Pharmacokinetics revealed dose-proportional exposure, and median BTK occupancy in peripheral blood mononuclear cells surpassed 95% across all dose levels at steady state. HZ-A-018 demonstrated acceptable safety and antitumor activity, supporting further clinical development.