Phase 1 Trial of Orelabrutinib in Combination with Rituximab, Methotrexate, and Dexamethasone in Patients with Newly Diagnosed Primary CNS Lymphoma Implementing Bayesian Design for Dose-Seeking

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.6225-6225
• Main Authors: Yuan, Yan, Wang, Qian, Zhuang, Dongxiao, Ding, Tianling, Chen, Hong, Zhu, Fengping, Zheng, Kang, Feng, Rui, Zheng, Jiajun, Zhang, Xiaoluo, Du, Zunguo, Zhu, Ping, Wu, Jinsong, Mao, Ying, Chen, Tong
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-181427

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal subtype of non-Hodgkin's lymphoma (NHL). High-dose methotrexate (HD-MTX)-based regimens are the first-line treatment for PCNSL, but remain suboptimal due to response instability and short effective remission duration. Orelabrutinib is a novel, potent, highly selective BTK inhibitor with a high CSF concentration. This study aims to investigate optimal combination dose of Orelabrutinib in combination with Rituximab, Methotrexate, and Dexamethasone (ORMD) as well as safety and efficacy of the regimen. Methods: This was a phase 1, investigator-initiated, dose-escalation study of ORMD, being conducted at Huashan Hospital, Fudan University (NCT05036577). Eligible patients must have histopathologically confirmed PCNSL-DLBCL by biopsy of brain lesions and be aged 18-75 years with adequate organ functions. Patients were treated for 6-8 cycles of induction therapy with 21 days per cycle, receiving rituximab (375mg/m 2 on day 1), dexamethasone (10-15mg on d1-d4), MTX (d2, 3.5g/m 2 or 5g/m 2), and orelabrutinib (once daily, after MTX clearance, 150mg/d, or 200mg/d), followed by orelabrutinib maintenance up to one year among CR/CRu patients. The primary objective was to determine the maximum tolerated dose (MTD) of the combination of orelabrutinib and MTX with R and D and investigate the safety and tolerability of this regimen using Bayesian Optimal Interval (BOIN) waterfall design to determine rule of dose escalation and movement among dose combination matrix to identify MTD contour. DLT was defined by the occurrence of severe toxicities during the first cycle: any grade 4 hematologic toxicity, grade 3 febrile neutropenia and grade 3 thrombocytopenia with hemorrhage, or any grade 3 non-hematologic toxicity that failed to respond to supportive therapy and possibly related to orelabrutinib and/or MTX (assessed according to NCI CTCAE V5.0). The secondary objectives included ORR/CR（u） and PFS/OS. Results: From October 2021 to July 2023, the study completed enrollment of all 13 patients. The median age was 60 years, and other basic characteristics are shown in Figure 1. All the patients had completed at least one cycle of ORMD treatment and were evaluable for DLT. The median cycle of ORMD was seven (range: 2.5-8). No DLT occurred among first 3 patients in cohort 1 (Orelabrutinib: 150mg/MTX: 3.5g/m 2) and dose escalation was allowed to cohort 2 (Orelabrutinib: 200mg/MTX: 3.5g/m 2). In co