Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with central nervous system (CNS)-penetrating profile and has demonstrated single-agent activity in recurrent/refractory CNS lymphoma in the monotherapy part of Study HZ-A-018-102 (CTR20210181), as previously reported at ASH2023. Here, we present updated results of the phase Ib combination part in patients with relapse/refractory (R/R) CNSL or treatment-naïve (TN) CNSL.
Method: The phaseIb part of HZ-A-018-102 aimed to explore the combination of HZ-A-018 with high-dose methotrexate (HD-MTX) in patients with CNSL. The treatment regimen consisted of a combined induction therapy, followed by HZ-A-018 maintenance. During the “Induction Phase”, patients received HD-MTX 3.0~3.5 g/m2 on day 1 of each cycle for four cycles (21 days per cycle). HZ-A-018 was initiated five days after HD-MTX administration or after methotrexate clearance, whichever occurred first. Following the completion of this induction phase, patients received HZ-A-018 once daily until disease progression (PD), intolerant toxicity or death (referred to as “Maintenance Phase”). HZ-A-018 was escalated in two dose levels (450mg QD and 600mg QD), using a “3+3” design. The safety evaluation of the combination was started in patients with R/R CNSL. Dose-limiting-toxicity (DLT) was assessed in the first cycle. If no DLT occurred, TN CNSL patients would be enrolled. Eligible patients must have relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) with at least one prior systemic therapy or be treatment naive, have a Karnofsky Performance Status（KPS）score of 60 or higher, and possess adequate end-organ function. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (AE) version 5.0. Causality assessment of AE was based on the judgement of investigators. Therapeutic responses were assessed according to the International PCNSL Collaborative Group Response Criteria (IPCG). Survival was monitored approximately every 8 weeks.
Results: Nineteen patients were enrolled in the phase Ib combination part, including nine with R/R PCNSL (four patients received 450 mg QD, five patients received 600 mg QD) and ten TN PCNSL (all received 600mg QD). The 600mg dose was the highest dose pre-defined in the study and the maximum tolerated dose (MTD) was not reached. In R/R PCNSL patients, the median age was 56 years (range: 43-74 years) and the median KPS was 70 (range: 60-90). All 9 patients (100%) presented with brain parenchyma, with a median sum of the product of diameters (SPD) of the target lesions of 972.0 mm2 (range: 132.7-2159.3). Two patients had relapse (22.2%) and seven patients had refractory disease (77.8%). The median number of prior antitumor regimens was one (range: 1-3), which included methotrexate (MTX)-based chemotherapy (100%) and rituximab (77.8%). In TN PCNSL patients, the median age was 61.5 years (range: 46-75 years) and the median KPS was 60 (range: 60-80). All 10 patients (100%) presented with brain parenchyma, with a median SPD of the target lesions of 1048.5 mm2 (range: 181.8-3341.8).
The combination of HZ-A-018 and HD-MTX was tolerated with a favorable safety profile. No DLT events was observed. There was no grade 3 or higher AEs. The most common treatment-related adverse events (TRAEs) (≥ 10%) were decreased platelet count, low white blood cell count, abnormal T waves on ECG. No patients experienced dose adjustment due to TRAEs and no treatment- related-serious adverse event (TRSAE) occurred.
In the R/R PCNSL patients (N=9), the overall response rate (ORR) was 55.6%, including 33.3% complete response (CR), 33.3% partial response (PR). Among five patients receiving 600 mg QD, the ORR was 80% and CR rate was 40%. Nine TN PCNSL patients were evaluable. Two patients completed the four cycles of the induction phase, both achieving PR, resulting in an ORR of 100%.
Conclusion: Preliminary data from this ongoing study of HZ-A-018 in combination with HD-MTX showed a tolerable safety profile and encouraging antitumor activity, not only in pretreated patients with R/R PCNSL but also in untreated TN PCNSL patients. The efficacy and safety of HZ-A-018 combination with HD-MTX in TN PCNSL patients will be investigated further in phase III study.
No relevant conflicts of interest to declare.
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