Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with central nervous system (CNS)-penetrating profile. The open-label and single arm phase I/II study (CTR20210181) is ongoing in China. Here, updated safety and efficacy results are presented in patients of relapse/refractory CNS lymphoma with HZ-A-018 monotherapy.

Method: HZ-A-018-102 is an ongoing phase I/II study to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of HZ-A-018 in CNS lymphoma. The primary objective for monotherapy part was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior systemic therapy. HZ-A-018 monotherapy was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity in the dose escalation study. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (AE) version 5.0. Causality assessment of AEs was based on the judgment of the investigators. The therapeutic responses were assessed according to the International PCNSL Collaborative Group Response Criteria (IPCG). Survival was followed approximately every 8 weeks.

Results: At the data cutoff date of 07 June 2024, 26 patients were enrolled from the phase I monotherapy, including 23 R/R PCNSL and 3 R/R SCNSL. 3 patients received 300mg/d, 12 patients received 450mg/d and 11 patients received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Patients were with a median age of 62.5 years (range: 36-80 years) and median KPS 80 (range: 60-90). 25 patients (96.2%) presented with brain parenchyma, with a median sum of the product of diameters (SPD) of the target lesions of 907.0 mm2 (range: 109.0-3474.9). One patient (3.8%) presented with isolated intraocular (IO) involvement. 12 patients had relapse (46.2%) and 14 patients has refractory disease (53.9%). The median number of prior antitumor regimens was 1 (range, 1-4), including methotrexate (MTX)-based chemotherapy (100%) and rituximab (92.3%). 12 of 26 patients (46.2%) experienced at least one treatment related adverse event (TRAE). The most common TRAEs (≥10%) were decreased platelet count (38.5%), decreased neutrophil count (19.2%), decreased white blood cell count (19.2%), hypokalemia (11.5%), hyperuricemia (11.5%), sinus bradycardia (11.5%), increased blood bilirubin (11.5%), and increased blood lactate dehydrogenase (11.5%). The majority TRAEs were grade 1 to 2 and only 5 patients experienced grade ≥3 TRAEs, which were neutropenia (11.5%), leukopenia and abnormal liver function (3.8% each). 2 DLT events were observed in 450mg and 600mg (1 event each), which were grade 4 neutropenia and grade 3 abnormal liver function respectively but the MTD was not reached at 600mg. 4 patients (15.38%) had dose interruption, and no patients had dose reductions or discontinued from the study due to TRAEs. In all patients (n=26) with a dose range of 300mg ~ 600mg, the overall response rate (ORR) was 50.0%, including 19.2% complete response (CR)/unconfirmed complete response (CRu), 30.8% partial response (PR). With a median follow-up of 19.0 months, the Kaplan-Meier-estimated median OS (mOS) was not reached (95%CI: 9.0, NE). All 11 patients with 600mg QD had achieved more higher and deeper responses, contributing to 72.7% ORR and 27.3% CRR, and mOS was not reached (95%CI: NE, NE).

Conclusion: Updated results further demonstrated that HZ-A-018 was well-tolerated and efficacious in CNS lymphoma patients. Patients had a median age over 60, a high refractory rate and majority of patients were previously treated with MTX and rituximab. At the clinical recommended dose of 600mg, patients had achieved great responses, and an improvement of the clinical outcomes, which has the potential to convert to a long survival benefit. A pivotal phase 2 R/R PCNSL registration study in China is currently planned.

Disclosures

No relevant conflicts of interest to declare.

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2024
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